Citrus reticulata Blanco: A Review on Chemical Composition and Biological Activities

Article type: Review Article

Keywords: biological activities, essential oil, flavonoids

Authors: José Walber Gonçalves Castro, Geane Gabriele de Oliveira Souza, José Galberto Martins da Costa, Fabíola Fernandes Galvão Rodrigues ⚬

Affiliations: Post Graduate Program in Biological Chemistry Department of Biological Chemistry Regional University of Cariri (URCA) Crato Ceará Brazil

License: © 2026 The Author(s). Chemistry & Biodiversity published by Wiley‐VHCA AG. CC BY 4.0 This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Article links: DOI: 10.1002/cbdv.202503156  |  PubMed: 41503727  |  PMC: PMC12780937

Relevance: Moderate: mentioned 3+ times in text

Full text: PDF (1.8 MB)

Introduction

Brazilian citriculture stands out as one of the largest producers worldwide. Orange trees, tangerine trees, acid limes, and true lemons are the main types of citrus cultivated in Brazil. The most recognized citrus varieties include sweet orange (Citrus sinensis), tangerine (Citrus reticulata), lemon (Citrus limon), grapefruit (Citrus paradisi), and pummelo (Citrus grandis or Citrus maxima) [ref. 1], which predominantly influence various systems such as the immune, reproductive, cardiovascular, and central nervous systems [ref. 2].

C. reticulata Blanco belongs to the Rutaceae family, which consists of more than 1600 shrub and small tree species and is native mainly to tropical, subtropical, and temperate countries. In Brazil, 33 genera and approximately 192 species are described [ref. 3]. Seasonal flowering is primarily controlled by environmental conditions, which directly influence its chemical composition; environmental cues regulate the initial development of the fruits and, therefore, the plants’ ability to reproduce multiple times throughout their lifespan, thus altering the biological activities of the species. However, in tropical areas, flowering becomes continuous, determined by the availability of moisture from sufficient rainfall or water supply, whereas in temperate regions or those with drought periods, flowering occurs at the onset of winter [ref. 4, ref. 5, ref. 6].

C. reticulata is an excellent source of vitamins C and A, proteins, dietary fibers, and essential minerals, including calcium, potassium, phosphorus, and magnesium, in addition to small amounts of B‐complex vitamins. On average, 100 g of tangerine is composed of 85.2 g of water, 13.34 g of carbohydrates, 0.81 g of protein, 0.38 g of dietary fiber, and 0.31 g of fat. The B‐vitamin complex contributes to infection prevention, promotes cellular health, and maintains adequate energy levels, nerve functions, hormone and cholesterol production, and also favors cardiovascular health [ref. 7, ref. 8, ref. 9].

The chemical components found in the peels and leaves of C. reticulata have been highlighted for their antinociceptive properties, as is the case with methyl‐N‐methyl anthranilate. Moreover, terpenoids, flavonoids, and phenolic compounds play an important role in defense against insects and microbial attacks. Noteworthy components include aldehydes, limonene, ketones, esters, alcohols, terpenes, β‐myrcene (8), 3‐carene (16), and α‐pinene (5), which provide, besides biological activities, the distinct aromas, and flavors of citrus fruits. Among these compounds, limonene (3) is the most predominant in tangerine essential oil (EO), followed by γ‐terpinene (2), p‐cymene (64), α‐pinene (5), and myrcene (8) [ref. 10, ref. 11, ref. 12].

C. reticulata Blanco exhibits numerous biological activities such as antimicrobial, laxative, aphrodisiac, antiemetic, astringent, tonic, anticholesterolemic, anti‐inflammatory, expectorant, and hepatoprotective properties, widely used by the population for food consumption, both fresh and in various preparations (jams and sweets). The peel and fruit are employed in perfumery, aromatherapy, and cosmetics [ref. 10, ref. 13].

Although numerous studies have highlighted the chemical composition of C. reticulata and its various biological activities, these data largely remain fragmented and concentrated in isolated experimental approaches, often lacking an integrated analysis that connects chemical composition with its pharmacological and therapeutic applications; however, this article proposes such a relationship. In addition, there is a shortage of studies exploring the influence of factors such as climate, soil, plant part used, and extraction methods on the variability of the identified bioactive compounds. Therefore, this review aims to analyze the main data available in the literature regarding the chemical composition and biological activities of C. reticulata, identifying patterns, potential applications, and areas that require further investigation.

The information in this review was obtained from the Science Direct, PubMed, and SciELO databases, covering the period from 2014 to 2024. Articles published in English or Portuguese were included, using the descriptors: chemical profile, biological activities, and C. reticulata Blanco. The search resulted in 1122 publications (716 in Science Direct, 388 in PubMed, and 18 in SciELO), which were subsequently analyzed according to the inclusion criteria: original articles with biological assays of extracts, EOs, fractions, or isolated compounds, as well as studies on chemical composition. Review articles, duplicates, publications outside the scope, or those that did not address biological activities were excluded. After screening, 49 articles met the established criteria. The systematic selection of these studies aims to consolidate a reliable scientific foundation for future research and sustainable applications of C. reticulata as a bioactive natural resource.

Results

Composition Chemical

The chemical investigation conducted on C. reticulata revealed the diversity of bioactive compounds distributed among the different fractions of the plant, ranging from the volatile constituents of the EO to complex nonvolatile secondary metabolites. The analysis allowed for the identification of monoterpenes and sesquiterpenes in the EO, including limonene, γ‐terpinene, α‐ and β‐pinene, sabinene, and α‐terpineol. These confer upon the species its characteristic aromatic profile, in addition to potential biological activities.

The nonvolatile extracts of the plant were demonstrated to contain substances of pharmacological and nutritional relevance, belonging to the classes of triterpenes, diterpenes, alkaloids, phenols, flavonoids, and coumarins. Among the flavonoids, methoxylated and glycosylated flavones and flavanones stand out, such as nobiletin, tangeretin, hesperidin, naringin, and quercetin, recognized for their antioxidant, anti‐inflammatory, and cardioprotective activities. Furthermore, coumarins and their derivatives were detected, substances with possible antimicrobial, antifungal, and hepatoprotective applications.

Other classes of compounds were also identified, including lipids (such as fatty acids and phytosterols), acridonic alkaloids, xanthine derivatives, tannins, depsides, as well as diverse constituents such as tocopherols, esters, and aliphatic alcohols. This complex chemical matrix highlights the multifunctional potential of C. reticulata, not only as a source of EO but also as a reservoir of active principles with therapeutic, cosmetic, food, and nutraceutical applications.

Thus, the following results are organized into chemical subgroups, in order to highlight the main constituents identified and their respective structural subclasses, reinforcing the phytochemical complexity of the species.

Volatile Components

From the gas chromatography–mass spectrometry (GC/MS) analysis of the EOs from C. reticulata fruit peels, it was possible to identify the presence of monoterpenes 1–13. Monoterpenes 1–3 are unsaturated monocyclic compounds, and monoterpenes 4–7 are bicyclic with hydrocarbon or epoxide functions. Monoterpenes 4 and 6 showed similar structures, differing in the olefinic bond at C‐1, being endocyclic ∆^1,2 and exocyclic ∆^1,7, respectively [ref. 14, ref. 15].

Monoterpenes 8–12 are acyclic compounds, with hydrocarbon, hydroxylated, or aldehydic functions, with one to three sp² unsaturations. Compound 13 is a tricyclic sesquiterpenoid, with a 4/9/3 junction, featuring an oxirane as a functional group [ref. 14, ref. 15]. In the investigations of Oliveira et al. [ref. 14], Sreepian et al. [ref. 15], and Kwangjai et al. [ref. 16], monoterpene 3 showed the highest chemical composition, with 85.7%, 72.53%, and 95.65% of the fruit peel EO, respectively.

In the analysis of the EO from C. reticulata fruit peels, carried out by Kwangjai et al. [ref. 16], the presence of monoterpenes 3, 5, 14–16 was identified and quantified. Compound 14 showed a cyclic structure with hydrocarbon function, with sp² bonds. The bicyclic monoterpenes 5 and 15 showed structural similarity, differing in the site of the double bond, exhibiting endocyclic ∆^1,6 and exocyclic ∆^1,10 bonds, respectively. Monoterpene 16 showed a bicyclic structure, hydrocarbon function, and endocyclic sp² unsaturation [ref. 15].

In a study carried out by Tao and Zhou [ref. 17], 22 terpenes and 5 aldehydes were elucidated by GC/MS‐FID, including acyclic, monocyclic, and bicyclic monoterpenes 1, 3–5, 7–9, 14–25, monocyclic sesquiterpenes 26–28, diterpenoid 29, and aldehydes 30–34. Monoterpene 3 (60.74%) was evidenced as the major compound in the composition of the EO of ripe C. reticulata fruits. The bicyclic monoterpenes 4, 5, 15–17 showed the same degree of unsaturation (3), with methyl and/or isopropyl branching. Furthermore, monoterpenes 16 and 17 have the same composition and similar structures, differing in the position of the sp² bond.

The acyclic monoterpenes 7, 8, and 18–24 are formed from hydrocarbons, primary or tertiary alcohol, or unsaturated monoaldehyde. In addition, monoterpenes 18 and 22 are geometric isomers, differing in spatial orientation. The monocyclic compounds 1–3, 14, 25–27 showed similar structures, differing in the degree of unsaturation, position of the sp² bond, functional group, and number of substituents. Furthermore, sesquiterpenes 26 and 27 resemble each other, differing in the position of the double bond, alternating between exocyclic or endocyclic [ref. 17].

Sesquiterpene 28 showed a 10‐carbon ring, 3 sp² unsaturations, and dimethyl and isopropyl branching [ref. 15, ref. 17]. Diterpenoid 29 was the most complex constituent, presenting an acidic portion (–SO₃H), two basic portions (–N–), and four saline portions (–CO₂Na), in addition to presenting polysubstituted benzene rings [ref. 17].

Aldehydes 30–34 showed simple structures with 8–12 saturated carbons, and aldehyde 35 showed an unsaturated 10‐carbon chain [ref. 17, ref. 18, ref. 19, ref. 20, ref. 21].

In the study carried out by Lin et al. [ref. 21], the metabolic composition of EOs from the fruit peels of two Citrus species, C. reticulata Blanco cv. Kinokuni (OECrBK) and C. reticulata Blanco (OECrB), was investigated. Even though they are of the same species, they showed some divergences in compounds and composition. A total of 35 compounds were identified, corresponding to the following terpenes 1–8, 10, 13, 15, 19, 23, 24, 26, 27, and 36–53, representing 98.68% (OECrBK) and 99.42% (OECrBK) of the EO composition.

Approximately 97% of the compounds are monoterpenes, and about 2% correspond to sesquiterpenoids. Monoterpene hydrocarbons were in greater abundance (93.96% and 95.94%, respectively), whereas oxygenated monoterpenes (2.88% and 0.95%, in that order) were less expressive [ref. 21].

In both EOs, monoterpene 3 was observed as the major component, corresponding to 79.13% (OECrBK) and 86.03% (OECrB). Regarding the structures of terpenes and aldehydes, compounds 1–35 were previously reported. Sesquiterpene 36 exhibits an acyclic structure, with an unsaturated hydrocarbon function. The acyclic monoterpene 37 showed a similar structure to 18, differing in the oxygenated functional group.

The monocyclic terpenes 38–41 showed the same structural skeleton, differing in the position of the sp² bonds, branching, and functional group, varying between hydrocarbon and aldehydic. Sesquiterpene 40 showed structural similarity to sesquiterpene 27, differing in an exocyclic double bond at ∆^12,13, present in compound 40. Sesquiterpenes 42–48 have similar structures, with two or three unsaturated hydrocarbon rings, except for sesquiterpene 45, which presented a hydroxyl [ref. 15, ref. 21].

According to the analysis of the EO from fresh C. reticulata Blanco cv. Dancy fruit peels, it was possible to identify terpenes 1, 3, 5, 8, 11, 12, 15, 18, 19, 23–25, and 36–38, previously characterized, as well as identifying monoterpene 3 (94.59%) as the main constituent of C. reticulata EO [ref. 18].

Compound 49, identified in OECrB, exhibited a different structure from the others, presenting an 11‐membered ring with 3 sp² unsaturations. Monoterpenoid 50, identified in OECrBK oil, exhibited a differentiated structure as it is a monophenol. Sesquiterpenes 51–53 are monocyclic and bicyclic structures, with hydrocarbon or oxirane organic functions [ref. 21].

Eighteen terpenes of varied structures were identified from the EO of C. reticulata fruits, such as terpenes 1, 3–6, 8, 19, 24, 36, 39, 42, and 43, previously mentioned, along with compounds 54–58. The monocyclic monoterpenes 54–56 are structurally similar, differing in the position of the sp² unsaturation, varying between endocyclic and exocyclic, functional group, and degrees of unsaturation. Sesquiterpenes 57 and 58 are unsaturated cyclic hydrocarbon compounds. Furthermore, compound 57 is similar to 41, differing in the sp² bond, varying between endocyclic and exocyclic. Monoterpene 3 (80.2%) was evidenced as the major constituent of the EO [ref. 19].

In the characterization analysis of the constituents of the EO from C. reticulata peel residues, monoterpenes 3, 5, 37, and 41, previously mentioned, along with monoterpenes 59–63, were identified. The monocyclic monoterpene 59 is structurally similar to monoterpenes 2 and 14, differing in the sp² olefinic bonds [ref. 20].

The acyclic monoterpene 60 showed structural similarity to compounds 7 and 8, distinguishing them by the location of one or two sp² bonds, varying between endocyclic and exocyclic. Monoterpene 61 is similar to monoterpene 19, differing in the functional group; compound 61 has an apolar character due to the presence of ethanoate, whereas substance 19 has a polar character due to the presence of hydroxyl [ref. 20].

Substance 62 is similar to monoterpenes 16 and 17, except for the position of the sp² unsaturated bond, which is located at C‐4, C‐3, and C‐2, respectively. Monoterpene 63 exhibited a saturated cyclohexane, interconnected to cyclopropane at C‐3 and C‐6, with three methyl branches and one endocyclic sp² unsaturated bond [ref. 20].

In the study of characterization of volatile metabolites present in the EO of fresh C. reticulata peels, subclasses of terpenes of varied structures were identified, including monoterpenes 1–7, 9, 11, 15, 16, 18–21, 23–25, 38, 39, 41, 50, 53, 60, and 63, and sesquiterpenes 26–28, 52, and 57, previously described, along with monoterpenes 64–75.

Monoterpenes 64–73 exhibited monocyclic or bicyclic unsaturated structures or an aromatic ring, with branching and hydrocarbon or oxygenated function. Monoterpenes 67 and 68 are geometric isomers, exhibiting a monounsaturated ring, with isopropyl substitution for hydroxyl. Monoterpene 74 is a geometric isomer of compound 7, whereas monoterpene 75 exhibits similarity to substance 60, differing in the presence of the carbonyl at C‐3 [ref. 22].

Terpenes 2, 3, 10, 21, 25, 27, 28, 37, 40, 50, 52, 63, and 76–78 were evidenced in the EO of C. reticulata Blanco and C. reticulata Chachi peels, with monoterpene 3 (88.4% and 75.1%, respectively) as the main constituent. Monoterpenoid 76 and sesquiterpenes 77 and 78 are low‐polarity terpenes, presenting acyclic or cyclic structures, with hydrocarbon or oxygenated function [ref. 23].

Nonvolatile Compounds

Terpenes

From the hexane extract of C. reticulata stem bark, it was possible to identify two polycyclic triterpenoids, compounds 79 and 80. Both had a secondary hydroxyl, exhibiting a 6/6/6/6/5‐membered ring (79) and a 6/6/6/6/6‐membered ring (80) [ref. 24].

In a study conducted by Phetkul et al. [ref. 25], two polycyclic triterpenoids, 81 and 82, were purified from dichloromethane (CH₂Cl₂) and acetone (Me₂CO) extracts. Triterpenoid 81 exhibited a unique six‐ring structure with a 6/5/6/6/6 junction, and the sixth ring being a 1,4‐epoxybut‐di‐ene branch. The main chain consisted of lactones, epoxides, and a ketone. Triterpenoid 82 had five rings, a 6/6/6/6/5 junction, with alcoholic and acidic organic functions.

The acyclic triterpene 83 and diterpenoids 84 and 85 were identified in the gradient solvent extraction (petroleum ether, chloroform, ethyl acetate [EtOAc], carbinol, and aqueous) of C. reticulata fruit peels. Triterpene 83 had an acyclic carbon chain, diterpenoid 84 consisted of five rings, a 6/6/6/5/4 junction, and two oxygenated groups, whereas diterpenoid 85 exhibited an acyclic chain containing an olefinic sp² (Srimathi and Gurunathan, 2020) [ref. 26]. These terpenes were the highest molecular weight constituents of the terpenic class found in this study.

Coumarins

According to the purification of the EtOAc:hexane fraction from C. reticulata stem bark, coumarins 86 and 87 were evidenced. Coumarins have a defined structural skeleton, consisting of an aromatic ring linked to an unsaturated ∆^3,4 lactone. Coumarin 86 had methoxyls at C‐6 and C‐7, and coumarin 87 had a dimethyl pyrone [ref. 24].

Seven coumarins, 88–94, were identified and purified from CH₂Cl₂ and Me₂CO extracts. Coumarins 88 and 89 have similar structures, differing in the oxygenated functional group. Coumarin 90 presented methoxyl, hydroxyl, and glutamic acid linked to an oxygenated group. Meanwhile, coumarins 91–94 showed mixed structures, with functions varying between hydroxylated, ether, and ester [ref. 25].

Flavonoids

Diverse flavonoids are identified from extracts of different solvents of dried leaves, fresh fruit peels, pulp, and seeds of C. reticulata. Eighty‐eight compounds of this class were identified in solvents of different polarities.

From the fractionation of the EtOAc extract of C. reticulata Blanco fruit peels, it was possible to identify flavonoids 95–100. These flavonoids had a polymethoxylated skeleton. Flavones 95–97 showed structural similarity, differing at C‐6 and C‐8, where they presented differences in functional position and number of methoxyls. Flavonols 98 and 99 have a methoxyl linked to C‐3 and polymethoxyl groups throughout the chain. Flavonol 100 stood out for presenting a C‐3‐O‐β‐glucose portion and another 3‐hydroxy‐3‐methyl‐5‐methoxy‐glutaroyl portion [ref. 27].

Seven flavonoids were identified from the fractionation of ethanolic (70%) and water extracts of fresh C. reticulata Blanco fruit peels. Flavanone‐O‐glycosides 101 and 102, flavone‐O‐glycoside 103, flavanones 104 and 105, flavonol 106, and flavone‐O‐methoxylated 107 were identified. These flavonoids have polyhydroxyls and methoxyls as functional groups [ref. 28].

The purification of the fractionation of the methanolic extract of dried C. reticulata leaves allowed the identification of 15 flavonoids of varied subclasses, such as flavones 97 and 107–111, flavonols 112–115, flavanones 116–119, and methoxylated chalcone 120, presenting polyhydroxyls or polymethoxylated groups [ref. 26, ref. 29].

According to a study conducted by Wang et al. [ref. 1], seven flavonoids were identified from the acetone extracts of the peels, pulps, and seeds of C. reticulata Blanco cv Chachiensis. Thus, flavone‐O‐methoxylated 95 and 107, flavanone‐O‐glycosides 101, 102, and 121, flavone‐O‐glycosides 103, and flavanones 105 were observed, with flavanone 101 (7497.15 µg g⁻¹) as the major compound. Flavones 95, 97, 107, and 119 were also evidenced in the ethanolic (95%) extract of C. reticulata peels, with flavone 107 (33.87%) observed as the major compound, followed by flavone 95 (20.98%). These flavones presented polysubstitutions, with polymethoxyls, hydroxyls, or both oxygenated groups [ref. 30].

Flavones 95, 97, and 107 and flavanones 101, 102, 104, and 121 were also reported in methanolic (80%) extracts of C. reticulata peels from 12 genotypes, along with flavan‐3‐ol 122, flavanone‐O‐glycosides 123, 124, and 125, flavones 126–128, flavonol 129, flavanones 130 and 131, and flavone‐O‐glycoside 132 and 133, with compound 100 (varying 17.53–55.98 mg g⁻¹ DW) evidenced as the major flavonoid in this extract. These flavonoids presented polysubstitutions, exhibiting different branching, such as glycosides, ketones, hydroxyls, and methoxyls [ref. 31].

Some of these compounds, 95, 97, 101, 102, 121–126, 130, and 132, were identified in at least 1 of the 12 genotypes of the methanolic (80%) extract of C. reticulata pulp, with compound 101 (6.721–22.13 mg g⁻¹ DW) as the major compound of this class [ref. 32].

Flavanone‐O‐glycosides 101, 124, and 130 were also identified in immature fruits of different sizes (8–24 mm) of C. reticulata, as well as flavone‐O‐glycoside 133. Flavanone 101 was observed with the highest content, decreasing as the fruit size increased [ref. 33].

From the polymethoxyflavonoid‐enriched fractionation of the ethanolic (95%) extract of C. reticulata Chachi fruit peels, it was possible to identify and purify flavones 95 and 98, previously reported in EtOAc extracts, along with flavones 134, 135, 136, and 137 and flavanones 138 and 139. Flavones 134 and 135 show structural and functional similarity, distinguished by the presence of a methoxyl at C‐3′ in compound 134. Methoxylated flavonol 98 and flavones 136 and 137 resemble the major compound 95 (49.28%), differing in the methoxyl binding site. Flavanones 138 and 139 exhibit similar structures and functions, differing in the position of a methoxyl [ref. 34, ref. 35].

In the study by Wang et al., [ref. 1] the metabolic composition of the ethanolic (95%) extract of C. reticulata fruit peels was evaluated, and flavonoids 101, 102, 121, 123–125, 130, 132, and 135, previously observed in methanolic (80%) extracts of C. reticulata peels, as well as flavonoids 140–150, were identified. Flavones 140–142 are similar, exhibiting polymethoxylated groups with a hydroxyl group, differing in the binding site of the functional groups.

Flavones 142 and 143 have polyhydroxyls and glycoside groups, whereas flavone 144 presented a very differentiated structure; in addition to the glycoside linked to C‐7, it exhibited seven silicons (Si) along the chain. Flavanones 145 and 146 presented similar structures, distinguishing by the branching of the glycoside and the presence of hydroxyl at C‐3′ in compound 146. Flavanone 147 presented methoxylated groups in cycles A and B, and flavones 148–150 showed some similarities, differing in the number of methoxylated groups and absence of hydroxyl in compound 150 [ref. 1].

Sixteen flavonoids were purified in studies conducted by Phetkul et al. [ref. 25], including flavonoids 95, 101, 103, 107, 109, 111, 113, 114, 119, 120, 123, 124, 136, 139, and 142, detailed previously, along with flavanone 151. Flavanone 151 is similar to flavone 148, differing in the presence of sp² unsaturation at C‐2, exhibited by compound 148 [ref. 35].

In the investigation carried out by Costanzo et al. [ref. 36, ref. 37], flavonoids 97, 102, 103, 105, 106, 126, and 128, previously mentioned, as well as compounds 152–179, were identified in aqueous/methanol (8:2) and methanol extracts of C. reticulata peels, pulp, and seeds. Anthocyanidins 152–164 are polyhydroxylated compounds with glycoside groups, whereas anthocyanidins 165 and 166 presented only hydroxyls. Flavan‐3‐ols 167 and 168 differ in the binding site of the phenol acid [ref. 25].

Flavanone 169 exhibited a similar framework to 144, distinguishing by the binding site of the trimethylsilyloxyphenyl cycle and the number of silicon atoms [ref. 36, ref. 37]. Compounds 170–175 are methoxylated flavonols, with one or two glycoside groups, polyhydroxylated. Flavones 176–178 presented, in addition to glycoside groups, hydroxylated or methoxylated functions, differing in the number of functional groups and spatial orientation. Isoflavone 179 exhibited hydroxylated functions and a glycoside linked to C‐8 [ref. 25].

In studies conducted by Apraj and Pandite [ref. 38], metabolites from the alcoholic extract of C. reticulata peel skin were characterized by hot air (Soxhlet) and cold air (maceration) extraction methods, with methoxylated flavonol 180 and flavones 181–183 being observed. Metabolites 180 and 183 are polymethoxylated, both showing similar structures, distinguished by the binding site and organic function, varying between hydroxyl and methoxyls.

Some flavonoids were identified in more than one type of extract, such as acetone, methanol, and ethanol, in different parts of the fruit, such as peels, pulp, seeds, and whole fruit, evidencing the richness of this class of compounds throughout the fruit.

Phenolic Acids and Diverse Compounds

In the study conducted by Ferreira et al. [ref. 28], different classes of compounds were isolated; in addition to the previously mentioned flavonoids, phenolic acids 184–186 were also identified. Phenolic acids 184 and 185 have similar structures, differing in the presence of hydroxyl or methoxyl at C‐3, respectively. Phenol 186 exhibited a mixed chain of polar character due to the presence of polyhydroxyls. These phenols were also identified in acetone extracts of C. reticulata Blanco cv Chachiensis peels, pulps, and seeds, along with phenolic acid 187. Phenol 187 is analogous to 184 and 185, differing by the absence of an oxygenated group at C‐3 [ref. 39].

Phenolic acids 184–187 were also reported in 12 genotypes of methanolic (80%) extracts of wild C. reticulata fruit peels and pulp, as well as phenols 188–191. Monophenol acid 188 presented four aromatic, methoxylated, propenoic, and hydroxylated substitutions, whereas phenols 189–191 exhibited simple structures, with a substituted aromatic ring, classified as biphenol acid, monophenol acid, and methoxylated monophenol acid, respectively. Compound 185 (1730.93–13 607.19 µg g⁻¹ DW and 778.06–2336.07 µg g⁻¹ DW, respectively) was the predominant compound in the 12 genotypes [ref. 31, ref. 32].

In a study conducted by Phetkul et al. [ref. 25], previously mentioned, phenolic acids 189 and 190, hydroxybenzaldehyde 192, phenolic methanoate 193, and depsides 194 and 195 were identified and purified. Phenols 189, 190, and 192 presented similar and basic structures, consisting of an aromatic ring, differing in the number of hydroxyls and functional group. Phenol 193 has a mixed chain, with an aromatic ring acyclic portion, with different oxygenated functions. Depsides 194 and 195 are composed of two aromatic units interconnected by an ester, in addition to presenting varied oxygenated functional groups.

The work of Costanzo et al. [ref. 36, ref. 37] identified phenols of varied subclasses, such as acid 186, previously described, along with acids 196–198 and 199, benzoate 200, polyphenols 201 and 202, and benzaldehyde 203. Phenolic acids 196 and 197 are simple compounds with similar structures and functional groups at the same binding sites, differing in organic function.

Tannin 198 presented a portion similar to acid 196, linked to the tannin group. Acid 199 presented a mixed chain, with interconnected rings by a methyl propenoate portion. Benzoate 200 exhibits the same structural skeleton as acid 196, distinguishing in the functional group. Polyphenols 201 and 202 are 1‐propranones linked to two phenols; the latter compound also exhibited a glycoside. Benzaldehyde 203 is structurally similar to benzoate 200, discerning in the presence of methoxyls in para substitutions and in the priority functional group [ref. 36, ref. 37].

Phenol 204 was identified in the EO of fresh C. reticulata fruit peels. This phenol presented a basic structure, with methanoate interconnected to the aromatic ring, showing an ortho relationship with the hydroxyl group [ref. 22].

Alkaloids

In the study by Ye et al. [ref. 29], a pyrano[2,3‐a]acridone‐type alkaloid 205 was observed for the first time in an MeOH extract of the Citrus genus, in addition to nine other known acridonic alkaloids 206–209, 210–214, and aldehyde 215. These alkaloids presented 6/6/6/6 or 6/6/6 polysubstituted junctions. Alkaloid 205 showed similarity to 206, differing in the linear pyrano[2,3‐a]acridone 205, whereas alkaloid 206 exhibited a pyrano[2,3‐c]acridone portion.

Alkaloids 206–209 presented the same structural skeleton, differing at C‐5 and C‐6 by their functional groups, exhibiting hydroxyls and/or methoxyls. Compounds 210–214 exhibited the same skeleton, differing in functional groups at C‐4, C‐6, C‐9, and C‐10, presenting methoxyls and/or hydroxyls. Xanthine 215 is a nitrogenous base, with a pyrimidine ring interconnected to an imidazole [ref. 29].

Acridonic alkaloids 207–209 were also reported in CH₂Cl₂ and Me₂CO extracts of C. reticulata Blanco peels, leaves, and branch barks, as well as acridonic alkaloids 216 and 217. These alkaloids presented a 6/6/6 structural configuration, with two aromatic rings, one at each end, and a central saturated cycle, differentiating them by their functional groups [ref. 25].

Lipids

In the study by Tahsin et al. [ref. 24], previously mentioned, in addition to terpenes and coumarins, the identification of two phytosterols 218 and 219, and one fatty acid 220 was also possible. Phytosterols 218 and 219 have the same structural skeleton, corresponding to a mixed chain, with a fused four‐ring framework, a 6/6/6/5 junction, with dimethyl branching, an acyclic group, and an oxygenated group. They differ in the unsaturation present in compound 218. Fatty acid 220 is a common, saturated 16‐carbon carboxylic acid [ref. 38].

From the gradient extract, carried out by Srimathi and Gurunathan [ref. 26], fatty acid 221, sterol 222, and cholesterol 223 were identified. Fatty acid 221 presented a structure with 20 carbons, acyclic, and saturated. Sterol 222 is similar to 219, differing in the oxygenated group. Cholesterol 223 resembles sterol 218, differing in an sp² unsaturation and absence of ethyl in the acyclic portion [ref. 37].

Diverse Classes

An active form of vitamin E 224 was among the variety of metabolites identified from C. reticulata fruit peels. This compound 224 consists of a monophenol, a pentahydrofuran ether, and a terpenic portion [ref. 26].

Diverse compounds of varied classes were identified in the work of Phetkul et al. [ref. 25]; among these, polymethoxylated benzene 225 was purified, consisting of an aromatic ring with varied oxygenated and hydrocarbon functional groups.

Aldehydes 32, 34, 35, and 33, previously reported, hydrocarbon 226, esters 227 and 228, and carboxylic acid 229. Hydrocarbon 226 contains 20 carbons and an sp‐type unsaturation at carbons ∆^9,10 [ref. 38]. Esters 227 and 228 are compounds of 5 and 18 carbons, respectively, with distinct oxygenated functional groups. Carboxylic acid 229 exhibited an 18‐carbon structure with 2 unsaturations [ref. 25, ref. 26].

In the work carried out by Apraj and Pandite [ref. 38], in addition to terpenes and flavonoids, various organic metabolites were identified, such as carboxylic acids 229 and 234, esters 230–232 and 110, organosulfur acid 233, pyran 235, aldehyde 236, alcohol 237, amide 108, hydrocarbon 109, and ketone 111.

Compounds 229–232, 234, 239, and 240 presented simple acyclic structures, differing in the number of carbons, functional groups, type of C–C bond, and branching. Acid 233 exhibits a relatively low molecular weight structure, with ketone functions and a sulfhydryl group (HS–). Compounds 235–237 presented monocyclic structures, varying between five and six members and different oxygenated functional groups.

Amide 238 presented three nitrogenous groups interconnected to the carbon portion. Ketone 241 is a complex structure, presenting two aromatic rings and two six‐membered rings, a 6/6–6/6 ring junction at each end, interconnected by an endocyclic bond and methoxyl functions [ref. 38].

In the research by Bhandari et al. [ref. 22], in addition to terpenes, aldehydes 30–34, previously described, hydrocarbon 242, and alcohols 243 and 244 were also identified. Hydrocarbon 242 consists of two aromatic rings, whereas alcohols 243 and 244 exhibit open, saturated chains with eight or ten carbons (Table 1).

Biological Activities

Larvicidal Activity

Biopesticides derived from natural products have gained prominence as an innovative alternative for pest control in agriculture. Although they have been used as insecticides for more than 20 years, their full potential has not yet been fully described, but they are recognized for their safety and environmental sustainability. Monoterpenes, sesquiterpenes, and phenylpropanoids have broad application as bioactive agents and can be used either individually or incorporated into specific formulations. When applied directly to the target, these compounds act as pesticides, larvicides, enzymatic inhibitors, or repellents, interfering with essential physiological processes. Their mechanism of action involves disrupting cell membrane integrity, inhibiting metabolic enzymes, and altering hormonal pathways that compromise the development and growth of the target organism, resulting in paralysis, starvation, or rapid death. In addition, some of these compounds affect the nervous system and cellular respiration, reinforcing their effectiveness as biological pest control agents [ref. 40].

Oliveira et al. [ref. 14] in the chromatographic analysis identified 13 compounds (1–13) in the EO of C. reticulata Blanco fruit peels, totaling 97.8% of its composition. The main component was limonene (3) (85.7%), followed by γ‐terpinene (6.7%) (2) and myrcene (8) (2.1%). The larvicidal activity against Aedes aegypti exhibited a lethal concentration (LC₅₀) of 58.35 µg mL⁻¹ and reached 100% mortality at 150 µg mL⁻¹, which can be justified by the compounds, mainly limonene (3) which can affect the physiological systems of the larvae, such as the inhibition of cell membrane function, interfering with permeability and causing cell dehydration.

The EOs of various Citrus species share chemical similarities, with monoterpenes (3, 5, 14–16) standing out, including limonene (3), as highlighted by Kwangjai et al. [ref. 16]. A high concentration of limonene was also observed in the fruit of C. reticulata, as reported by Tao and Zhou [ref. 17]. A more recent study (Prommaban and Chaiyana 2022) [ref. 41] involving microemulsions of EOs from Citrus peels and leaves also identified limonene (3) as a key compound responsible for biological activities. Castro et al. [ref. 42] describe that limonene (3) is partially responsible for larvicidal effects; its activity is mainly related to the disruption of cellular membrane integrity and larval cuticular structures, leading to ion loss and dehydration, which culminate in cell death.

Leishmanicidal Activity

Natural products, especially medicinal plant extracts, have shown promising leishmanicidal effects. The antiparasitic action in vitro and in vivo acts without causing toxicity to host cells. Furthermore, plants and their by‐products induce an increase in nitric oxide (NO) production in infected macrophages, enhancing the immunological response against the parasite. These findings highlight the potential of natural products in the development of new treatments for leishmaniasis, as pointed out by [ref. 43].

The studies by Oliveira et al. [ref. 14] demonstrated promising activity against promastigote forms of Leishmania amazonensis, with an IC₅₀ value of 8.23 µg mL⁻¹, a result considered highly active. However, the research notes that the EO from the peels of C. reticulata fruits may show variable results due to processing quality, as the extraction process often occurs without proper regulation. The assays indicate that the high antileishmanial activity observed in this study may be attributed to the significant presence of limonene (3), a monoterpene known for its action against Leishmania parasites. Limonene alters cellular membrane permeability, promoting redox imbalance in parasitic cells with increased reactive oxygen species (ROS), mitochondrial damage, and reduced ATP synthesis, ultimately leading to oxidative stress and cell death.

Anti‐Inflammatory Activity

Wen et al. [ref. 44] present a study suggesting that the inhalation of the EO from C. reticulata fruit peels has significant anti‐inflammatory effects on the airways and pulmonary emphysema in animal models of Chronic Obstructive Pulmonary Disease (COPD). The main results indicate a reduction in inflammation, possibly mediated by the modulation of macrophage activity, decreasing levels of IL‐18, IL‐17A, IL‐12p70, and GM‐CSF, suppressing the relative mRNA expression of interferon‐γ (IFN‐γ), IL‐4, and MMP‐12, and increasing IL‐10 mRNA expression, in addition to improving body weight and mental state of COPD rats; however, the study does not describe to which constituents this activity was attributed.

Hilel et al. [ref. 45] worked with the ethanolic extract of mature C. reticulata peels against the anti‐inflammatory effect on the mechanical hyperalgesia in a dextran sodium sulfate (DSS)‐induced colitis model; this showed systemic activity because nobiletin (95), a flavonoid found in the peels and in plants of this genus, has the ability to reduce several inflammatory markers in animal models of osteoarthritis. The study highlighted that naringenin (104) inhibited the elevation of inflammatory cytokine expression, which is aligned with the protective effect of the plant on intestinal barrier integrity.

Kwangjai et al. [ref. 16] evaluated the brain wave modifications and sleep parameters induced by the use of C. reticulata Blanco EO. The inhalation of the EO induced electroencephalogram patterns similar to the control, with significant changes in the delta, theta, alpha, beta1, and gamma frequency bands in the frontal and parietal cortex of rats, which confers anti‐inflammatory activity. Regarding sleep parameters, EO reduced REM sleep latency and increased both total sleep time and the number of sleep episodes, unlike diazepam, which increased wakefulness and non‐REM sleep episodes. This activity was attributed to D‐limonene (3) (95.7%) as the main component of C. reticulata EO, with α‐pinene (5) (0.5%), β‐pinene (15) (1.1%), and δ‐3‐carene (16) (1.5%) obtained by GC–MS analysis.

The dried pericarps of the species also demonstrated an inhibitory effect on foam cell formation derived from macrophages and promoted HDL‐mediated cholesterol efflux causing inflammation, exhibiting antiatherogenic capacity by interfering with RAW264.7 foam cell formation through inhibition of lipid uptake and promotion of HDL‐mediated cholesterol efflux, as described [ref. 46].

Duan et al. [ref. 34] investigated the polymethoxyflavones (PMFs) (95, 98, 134–139) present in the peels of C. reticulata fruits and isolated eight distinct PMFs, identified through nuclear magnetic resonance (NMR) and mass spectrometry techniques. Among these, the compound 6,7,8,3′,4′‐pentamethoxyflavanone (138) stands out, being isolated for the first time from the peels of this specific variety. The compound 3,5,6,7,8,3′,4′‐heptamethoxyflavone (98) demonstrated potent inhibitory activity against sterol regulatory element‐binding proteins, whereas 5‐hydroxy‐6,7,8,3′,4′‐pentamethoxyflavone (134) exhibited strong antiproliferative activity against tumor cell lines, with the ability to inhibit NO production. The efficacy varied mainly according to the number of methoxy groups present in the molecules, indicating anti‐inflammatory and antiproliferative properties.

Ferreira et al. [ref. 28] investigated the extraction efficiency of phenolic compounds from the peels of C. reticulata Blanco. The main compounds identified were hesperidin (101), rutin (103), naringenin (104), and tangeretin (107), which together accounted for approximately 86% of the total phenolics extracted from the species. In addition, the extracts demonstrated dose‐ and cell line–dependent antiproliferative activity, with IC₅₀ values of 174.5 ± 5.8 µg mL⁻¹ for BT‐474 cells (breast cancer), 391.9 ± 15 µg mL⁻¹ for Caco‐2 cells (colorectal cancer), and above 500.00 µg mL⁻¹ for HepG2 cells (liver cancer), indicating anti‐inflammatory activity. These compounds act by modulating the NF‐κB and MAPK pathways, reducing pro‐inflammatory cytokines and inducing apoptosis, which results in inhibition of cell growth, decreased tumor proliferation, and anti‐inflammatory action.

Hawas et al. [ref. 47] investigated flavonoids and their hepatoprotective efficacy against thioacetamide‐ (TAA‐) induced liver injury in rats. The isolated flavonoids showed a significant reduction in serum levels of hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and bilirubin, which had been elevated due to TAA administration. A decrease in tumor necrosis factor‐α (TNF‐α) levels and a significant reduction in hepatic hydroxyproline content were also observed, indicating reversal of induced fibrosis. Histological examination of liver tissues corroborated the anti‐inflammatory effect of the ethanolic extract, showing improved cellular integrity and reduced tissue damage.

Wu et al. [ref. 48] evaluated the protective effect of the flavonoid composition from the peels of C. reticulata. The levels of pro‐inflammatory cytokines, including TNF‐α, IFN‐γ, interleukin‐1β (IL‐1β), and interleukin‐6 (IL‐6), were significantly reduced in mice treated with the flavonoid solution. Regarding the hepatoprotective effect, there was a significant reduction in serum levels of ALT and AST, enzymes indicative of liver injury. The peel extract contains flavonoids such as narirutin (124) (10 mg g⁻¹), hesperidin (101) (84.9 mg g⁻¹), nobiletin (95) (27.3 mg g⁻¹), tangeretin (107) (28.3 mg g⁻¹), and 5‐demethylnobiletin (111) (8.4 mg g⁻¹), which are responsible for the protective activity.

The ethanolic extract of C. reticulata pericarp also showed anti‐inflammatory activity. The expressions of type I and III collagen proteins were suppressed, suggesting an effective inhibition of collagen deposition in lung tissue, resulting in the suppression of pyridinoline production, a collagen cross‐linking marker, in addition to a decrease in the protein expressions of transforming growth factor beta 1 (TGF‐β1) and Smad3 in the lungs. These findings suggest antifibrotic properties, acting in the inhibition of collagen synthesis, cross‐linking, and deposition, possibly mediated by the downregulation of the TGF‐β1/Smad3 pathway, as pointed out by Li et al. [ref. 49].

The scientific evidence reported by Srimathi and Gurunathan [ref. 26] on the methanolic extracts from the fruit peels and seeds of C. reticulata describes their ability to neutralize toxins from the Indian cobra Naja naja venom. The peel extracts of citrus species significantly inhibited the phospholipase A₂ (PLA₂) (75%), protease (71%), and hemolytic (80%) activities induced by the venom. The presence of β‐sitosterol (219), hexadecanoic acid (240), eicosanoic acid (221), α‐tocopherol (224), and squalene (83) contributes to the neutralization of the venom’s cytotoxic and inflammatory effects.

The effects of the ethanolic extract from the dried peels of C. reticulata on the inflammatory response of macrophages, as reported by Lee et al. [ref. 50], showed a significant decrease in the production of the pro‐inflammatory cytokine IL‐6, while stimulating a low concentration of lipopolysaccharide (LPS) (1 ng mL⁻¹) and increasing the expression of Ras guanine nucleotide–releasing protein 3 (RasGRP3). Nobiletin (95) was described in the study as one of the main components contributing to the observed anti‐inflammatory effects, modulating the production of pro‐inflammatory cytokines in macrophages.

Zhou et al. [ref. 51] isolated and purified a predominant polysaccharide from the peels of C. reticulata, identified as an arabinogalacturonan. The structure of the polysaccharide was determined by NMR spectroscopy, revealing a main chain of (1 → 4)‐α‐d‐galacturonan with α‐l‐arabinofuranosyl side branches. This compound showed no toxicity toward macrophages; however, it significantly promoted NO production in a dose‐dependent manner, indicating potential immunomodulatory activity.

Antioxidant Activity

Ferreira et al. [ref. 28] demonstrated that there are no significant differences in the extraction efficiency of phenolic compounds when two different solvents are used. The main compounds identified in the fruit peel extracts, ethanolic and aqueous, were hesperidin (101), naringenin (104), tangeretin (107), and rutin (103), which together represented approximately 86% of the total extracted phenolics. Furthermore, the application of solid‐phase extraction allowed a 4.5‐fold enrichment in phenolic compounds, and the antioxidant activity of the extracts presented an IC₅₀ of 174.5 ± 5.8 µg mL⁻¹ (BT‐474), 391.9 ± 15 µg mL⁻¹ (Caco‐2), and >500.00 µg mL⁻¹ (HepG2).

Citrus compounds may have different chemical contents when found in different tissues. Zhang et al. [ref. 52] highlight that fruit peels showed the highest average total phenolic contents (27.18 mg gallic acid equivalents per gram dry weight) and total flavonoids (38.97 mg rutin equivalents per gram dry weight), whereas pulp, seed, and juice residues: The contents varied among the different genotypes analyzed, with values lower than those found in the peels. As for antioxidant capacity, the peels showed the highest antioxidant capacity, with DPPH^• values equivalent to 21.92 mg of ascorbic acid equivalent antioxidant capacity per gram dry weight and ABTS^•+ values equivalent to 78.70 mg per gram dry weight. In other tissues, the antioxidant capacity varied, generally being lower than that observed in the peels.

The findings of Zhou et al. [ref. 51] described the structural variations of polysaccharides present in the peels of C. reticulata. A linear (1 → 4)‐α‐d‐galacturonan structure was isolated and characterized, revealing significant immunomodulatory activity in two distinct polysaccharides derived from this backbone—one of the arabinogalactan type and the other of the arabinogalacturonan type. These compounds exhibited antioxidant and immunoregulatory properties, demonstrating their ability to protect cells against hydrogen peroxide–induced oxidative damage by enhancing the activity of antioxidant enzymes.

The investigations by Mahdi et al. [ref. 53] suggest improvements in the antioxidant properties of nanocapsules containing C. reticulata EO (CEO) through the addition of Cinnamomum verum (cinnamon) and Dianthus caryophyllus (clove) EOs. The incorporation of cinnamon and clove EOs increased the total phenolic content of the nanocapsules by 1.75 and 1.54 times, respectively, compared to nanocapsules containing only CEO. The addition of cinnamon and clove oils resulted in a significant increase in the antioxidant activity of the nanocapsules, increasing it by 3.57 and 2.08 times, respectively.

Zang et al. [ref. 54] investigated the phenolic compounds present in the methanolic extract from the fruit peels of 14 wild Citrus genotypes. Among the main phenolic compounds identified were nobiletin (95), hesperidin (101), eriocitrin (123), narirutin (124), and ferulic acid (185), which were responsible for the combined antioxidant potency index (APC), showing significant variations ranging from 58.84 to 98.89 among the analyzed species. The mechanism of action of these compounds involves electron or hydrogen atom donation to neutralize ROS, as well as metal ion chelation that catalyzes oxidative reactions. They also modulate endogenous antioxidant enzymes (such as SOD, CAT, and GPx), resulting in reduced oxidative stress and protection of cellular structures against oxidative damage.

Prommaban and Chaiyana [ref. 41] presented limonene (3) as the main component, varying between 72.5% and 95.7%, depending on the source (fresh leaves, fresh peels, or dried peels). The oils from the leaves and fruit peels of Citrus species (C. aurantifolia and C. reticulata) demonstrated strong antioxidant activities, including the ability to neutralize free radicals and inhibit lipid peroxidation. The oil from dried C. reticulata peels significantly inhibited collagenase and tyrosinase activities, suggesting potential for reducing wrinkles and skin blemishes, significantly reducing skin irritation in human volunteers, indicating that microemulsification can improve the safety of topical use of these EOs.

Najem et al. [ref. 55] elucidated that the EO from the fruit peels exhibited higher antioxidant activity when compared to the pure major compound. The chemical profile analyzed by GC/MS identified limonene (3) as the main component (81.90%). The EO demonstrated a potent antioxidant effect in the DPPH^•, ABTS^•+, and FRAP assays, with mean inhibitory concentrations (IC₅₀) of 2.01, 3.47, and 4.71 mg mL⁻¹, respectively. The mechanism of action involves electron and hydrogen atom donation to neutralize free radicals (such as DPPH^• and ABTS^•+), in addition to the reduction of ferric ions (Fe³⁺ → Fe²⁺) in the FRAP assay. This combined action promotes the stabilization of reactive radicals, interruption of oxidative chain reactions, and protection of biomolecules against oxidative stress, thereby justifying the high antioxidant capacity observed.

The polysaccharides from C. reticulata fruit peels demonstrated significant antioxidant activities, including the ability to reduce ferric ions (FRAP), neutralize hydroxyl radicals (^•OH), DPPH^• radicals, and superoxide radicals (O₂ ⁻), in a concentration‐dependent manner. These activities suggest that polysaccharides can act as effective natural antioxidants [ref. 56].

The peel oil of C. reticulata may act as an antiatherogenic agent by modulating oxidative stress. Molecular docking analyses suggested that the oil’s compounds—such as α‐farnesene (36) and neryl acetate (37), as well as the major component limonene (3) and its metabolites—may inhibit lanosterol synthase, contributing to reduced cholesterol synthesis and decreasing the formation of foam cells, which are precursors of atherosclerotic plaques. In addition, the oil prevented copper sulfate–induced LDL lipid peroxidation, as described by Castro et al. [ref. 42].

Xi et al. [ref. 32] investigated the phenolic composition and antioxidant properties of the fruit pulps from 14 C. reticulata Blanco genotypes. The chemical profile identified hesperidin (101) as the predominant flavonoid, whereas ferulic acid (185) was the most abundant phenolic acid in the methanolic extract of C. reticulata peels. Overall, the pulps of the Nieduyeju, Guangxihongpisuanju, and Wangcangzhoupigan genotypes contain higher levels of phenolic compounds and exhibit greater antioxidant capacities compared with Satsuma and Ponkan, indicating their potential as rich sources of phytochemicals and natural antioxidants. These effects reduce oxidative stress, protect lipids, proteins, and DNA from damage, and maintain cellular redox balance, supporting the high antioxidant capacity observed in pulps richer in phenolics.

Job et al. [ref. 20] found that the antioxidant properties of the EO from fruit peels were attributed to the presence of compounds such as D‐limonene (3), α‐pinene (5), α‐myrcene (60), and cis‐terpinene (39) which have radical scavenging capacity, ferric reducing antioxidant power, and lipid peroxidation inhibition, demonstrating that the thick outer layer that is often discarded due to its low economic value generally contributes to potential health benefits.

Rashed et al. [ref. 57] in GC–MS analysis revealed D‐limonene (3) as the main component of C. reticulata leaf EO, with concentrations ranging between 50.3% and 65.7%, depending on the applied treatment. Nanoemulsions developed using octenyl succinic anhydride modified starch (OSA‐MS) and almond oil demonstrated significant antioxidant activity in the β‐carotene/linoleic acid system, with low degradation rates, indicating high resistance to oxidation compared to the control. These findings suggest that the combination of enzymatic pretreatment and ultrasound‐microwave techniques improves the extraction efficiency of C. reticulata leaf EO.

There is a relationship between the impact of different drying techniques on flavonoid, total phenol contents (TPCs), and the antioxidant capacity of green C. reticulata Blanco fruits. In the findings of Kumar et al. [ref. 33], hesperidin (101) was the predominantly identified flavonoid; lyophilized fruit samples with 12 and 14 mm diameter showed the highest contents, with 27.03% and 27.20%, respectively. In contrast, the same samples subjected to oven drying showed a reduced content of 17.99%. Lyophilized fruits exhibited a TPC: ranging between 50.50 and 54.19 mg of gallic acid equivalents per liter. It was also possible to observe a significant positive correlation between hesperidin (101) contents and antioxidant assay results.

Costanzo et al. [ref. 36] demonstrated that antioxidant capacity was higher in green fruits, whereas seeds significantly increased their antioxidant activity during maturation, reaching their peak in fully ripe fruits. The fruit peels exhibited the highest levels of polyphenols and flavonoids, whereas the seeds contained ascorbic acid and condensed tannins. These antioxidant effects are attributed to compounds such as anthocyanins, naringin (102), rutin (103), tannins, polyphenols, delphinidin‐3‐O‐glucoside (154), cyanidin‐3‐O‐glucoside (155), quercetin‐3‐glucoside (173), and gallic acid (196), which are responsible for chelating pro‐oxidant metals.

Phenolic compounds are described as the main contributors to the antioxidant capacity of citrus fruits due to their actions in neutralizing free radicals, donating electrons or hydrogen atoms, and chelating pro‐oxidant metals. It is worth highlighting the flavanones hesperidin (101), naringin (102), neohesperidin (121), didymin (130), and poncirin (132), which are present in C. reticulata. The study by Wang et al. [ref. 1] identified 39 flavonoid compounds, including 4 flavones, 9 flavanones, and 26 PMFs.

Apraj and Pandita [ref. 38] investigated the anti‐aging potential of C. reticulata Blanco fruit peels through alcoholic extracts obtained by two methods: Soxhlet and maceration. The extract obtained by Soxhlet showed phenolic compounds and flavonoids when compared to maceration. The extracts demonstrated significant antioxidant capacity in various assays due to the presence of PMFs. The alcoholic extract showed an EC₅₀ value of 250.33 ± 40.16 µg mL⁻¹, indicating strong DPPH^• free radical scavenging activity, an EC₅₀ value of 221.27 ± 11.25 µg mL⁻¹, suggesting effectiveness in neutralizing superoxide anions, in addition to inhibiting enzymes such as collagenases and elastase. Both alcoholic extracts of fruit peels showed similar activities in the ABTS^•+ assay.

Phetkul et al. [ref. 25] report the isolation of a new depside, named depcitrus A (195), along with 31 already known compounds, from C. reticulata Blanco fruit peels, leaves, and branch barks. In this study, they found eight polymethoxy flavonoids, six acridone alkaloids, four flavonoids, four flavonoid glycosides, four coumarins, two isocoumarins, two depsides, two resorcinol derivatives, one coumarinic glycoside, one limonoid, one triterpenoid, and three benzoic derivatives. These compounds were evaluated for their ability to neutralize the DPPH^• free radical, and the results showed that the activity was very weak, with DPPH^• scavenging percentages ranging between only 0.65% and 23.2%.

Some studies evaluate antioxidant activity modulated by abiotic factors. Costanzo et al. [ref. 37] investigated how light‐emitting diode (LED) radiation applied after harvest can affect and modulate the levels of antioxidant compounds in C. reticulata fruits. LED light significantly modulated the levels of antioxidant compounds such as phenolics and carotenoids, leading to an increase in the total antioxidant activity of the fruits (peels), evidenced by free radical scavenging tests. These effects indicate that LED light can strengthen the natural defense mechanisms of the fruits and prolong their quality and shelf life during storage.

Lin et al. [ref. 21] investigated the chemical composition and antioxidant activity of EOs extracted from the fruit peels of four varieties of species within the Citrus genus. The chemical profile revealed that monoterpene hydrocarbons were the main components in all EOs, with limonene (3) being the predominant compound. All EOs demonstrated dose‐dependent DPPH^• and ABTS^•+ free‐radical scavenging capacity, emphasizing that Citrus species may have potential applications in the pharmaceutical and food industries by stabilizing formed free radicals and protecting biomolecules.

Bhandari et al. [ref. 22] also described the antioxidant activity, which was superior to that of the positive control, quercetin (5.60 µL mL⁻¹). C. reticulata showed the second‐best activity in the DPPH^• radical scavenging assay. This activity can be justified by GC–MS analysis which revealed limonene (3) as the predominant compound in all EOs, ranging from 63.7% to 89.1%. Other major constituents included γ‐terpinene (2) (0.24%–6.43%), β‐pinene (15) (0.15%–6.09%), and linalool (19) (0.35%–3.5%).

Antimicrobial Activity

Oliveira et al. [ref. 14] described that the EO from the fruit peels of C. reticulata exhibited promising activity against promastigote forms of L. amazonensis, with a 50% inhibitory concentration (IC₅₀) of 8.23 µg mL⁻¹. This activity is justified by its composition of 85.7% limonene (3), 6.7% γ‐terpinene (2), and 2.1% myrcene (8), which have the ability to alter plasma membrane permeability and fluidity, leading to the loss of essential cellular components and collapse of the microorganism’s ionic homeostasis.

The literature describes findings of microorganisms acting in the modulation of abiotic stress on the development of Citrus species. Hasan et al. [ref. 58] evaluated partial tolerance to abiotic stresses in C. reticulata through Agrobacterium‐mediated transformation. Transgenic seedlings showed greater tolerance to drought and salinity compared to control plants, indicating that the microbial genes PsCBL and PsCIPK contributed to resistance to these abiotic stresses. These results point to genetic modification as a promising strategy to develop varieties more adapted to adverse environmental conditions.

The antifungal activity of the EO from C. reticulata fruit against Penicillium sp. was described by Tao and Zhou [ref. 17]. The findings report the dose‐dependent inhibition of Penicillium italicum and Penicillium digitatum growth. The antifungal activity was attributed to compounds such as limonene (3), citral (18 and 22), linalool (19), and terpenes. The fruit oil also caused structural damage to hyphae, increased membrane permeability, and loss of cellular components, suggesting cytotoxic action by compromising the integrity of fungal cells.

Wu et al. [ref. 30] also evaluated the antifungal activity of polymethoxylated flavones extracted from C. reticulata fruit peels. The study identified tangeretin (107) and nobiletin (95) as the main polymethoxylated flavones. The ethanolic extract showed high efficacy against Aspergillus niger, with a minimum inhibitory concentration (MIC) of 0.12 mg mL⁻¹, significantly lower than that of isolated tangeretin (107) (1.5 mg mL⁻¹). The data indicate changes in the fungal cell membrane, increasing potassium loss and electrical conductivity, reducing chitin production, and weakening the cell wall.

The EOs from the fruit peels of Citrus aurantiifolia and C. reticulata, which contain a high content of limonene (3), exhibited antimicrobial activity. Among the limonene enantiomers, (R)‐limonene showed greater antimicrobial action in internal exposure assays. The data indicate that these oils act through multiple mechanisms, such as disruption of the cell membrane and volatile action, and they have potential for use as antimicrobial agents, as noted by Fouad and Camara [ref. 19].

The EO obtained from the fruit peels of C. reticulata exhibited antibacterial activity against microorganisms such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella enterica, as demonstrated through agar diffusion assays and determination of the MIC. These findings indicate that the EO from C. reticulata peels has promising therapeutic potential, as it acts by disrupting the bacterial cell membrane, causing leakage of ions and cytoplasmic contents, in addition to enzymatic inhibition of energy metabolism. These effects are attributed to its main constituents: S‐limonene (3), α‐pinene (5), cis‐terpinene (39), and α‐myrcene (60), according to Job et al. [ref. 20].

The ethanolic extract obtained from the fruit peels of C. reticulata Blanco, rich in polymethoxylated flavones such as nobiletin (95) and tangeretin (107), contains compounds known for their antimicrobial activity by inhibiting enzymes involved in nucleic acid and protein synthesis, interfering with biofilm formation, and suppressing bacterial multiplication. Genotoxicity assays revealed that the extract did not induce mutations in bacteria nor cause genetic alterations in animal models, which reinforces its potential as a safe therapeutic agent, including for antimicrobial applications, as reported by Nakajima et al. [ref. 35].

The study by Phetkul et al. [ref. 25] identified a new compound from the depside class, named depcitrus A (195), isolated from different parts of the plant C. reticulata Blanco, in addition to several other previously known metabolites. Among the isolated compounds, some were subjected to antimicrobial activity tests, demonstrating the ability to inhibit the growth of pathogenic microorganisms such as S. aureus by disrupting the integrity of the bacterial cell wall and membrane, leading to membrane depolarization. These findings reinforce the potential of the phenolic compounds present in C. reticulata as natural agents with antimicrobial activity.

The EOs from the fruit peels of four species (C. reticulata Blanco cv, C. reticulata Blanco, Citrus japonica Thunb, and C. sinensis Osbeck cv. Newhall) were tested against five bacteria: Bacillus subtilis, S. aureus, E. coli, P. aeruginosa, and Salmonella typhimurium. The EOs exhibited varying antibacterial activities, with MIC values differing for each species. Among these species is C. reticulata, whose EO destabilizes the bacterial cell membrane, increases its permeability, and causes leakage of ions and proteins, ultimately leading to metabolic inhibition and cell death, as reported by Lin et al. [ref. 21].

Bhandari et al. [ref. 22] also evaluated the antibacterial activity of four species: C. grandis Osbeck red pulp, C. reticulata Blanco, C. sinensis Osbeck, and C. grandis Osbeck white pulp. The EOs were tested against the bacteria S. aureus, E. coli, Klebsiella pneumoniae, Shigella sonnei, and Salmonella typhi using the disk diffusion method. The results indicated that the oils exhibited antibacterial activity, justified by their interaction with bacterial membrane lipids, resulting in the loss of essential intracellular components. The EO of C. reticulata Blanco showed notable activity against S. typhi, reducing the MIC from 19 to 10 mm compared with the neomycin control.

The antibacterial activity and synergistic interaction of citrus EOs and limonene (3) with gentamicin against clinical isolates of methicillin‐resistant S. aureus (MRSA) were also evaluated. Sreepian et al. [ref. 15] identified 12 compounds in the EO extracted from the fruit peels of C. reticulata, with limonene (3) being the predominant component responsible for destabilizing the lipid bilayer of the bacterial membrane. Antibacterial assays revealed that both the oil and limonene (3) exhibited significant inhibitory effects against clinical isolates of MRSA and MSSA, with MICs ranging from 1.0 to 32.0 mg mL⁻¹. The combination of gentamicin with the oil or with limonene (3) resulted in a synergistic interaction against MRSA and MSSA isolates (FIC indices: 0.012–0.258 and 0.012–0.375).

Mahdi et al. [ref. 53] investigated the enhancement of EO nanocapsules from C. reticulata fruits (CEO) through the addition of EOs from C. verum (cinnamon) and D. caryophyllus (clove), resulting in a significant increase in antifungal activity against different species. Against Candida albicans, antifungal efficacy increased 3.13‐fold with C. verum oil and 2.43‐fold with D. caryophyllus oil; for Zygosaccharomyces rouxii, a 1.24‐fold increase was observed with both oils. In the case of A. niger, activity increased 2.76‐fold with C. verum oil and 1.32‐fold with clove oil, whereas for Penicillium roqueforti, the increase reached 2.97‐fold with cinnamon oil and 2.09‐fold with clove oil. These results indicate a potential synergy between the EOs, promoting greater fungal membrane disruption due to increased cellular permeability and enzymatic protein denaturation, leading to greater inhibition of pathogenic fungal growth and making the nanocapsules more effective for fungal control.

Other Findings

Ye et al. [ref. 29] explored the chemical composition of the methanolic extract of C. reticulata leaves. The investigation resulted in the discovery of a new acridone alkaloid, named reticarcidone A (205), being the first pyrano of the Citrus genus. In addition, nine already known acridone alkaloids and fifteen flavones were isolated from this same extract. Some of these compounds showed moderate cytotoxicity against five human cancer cell lines (breast, liver cancer, promyelocytic leukemia, lung cancer, and colon cancer). These results expand the knowledge about the chemical diversity of C. reticulata and indicate a promising potential for anticancer pharmacological applications.

Research suggests that citrus fruit residues, such as peels and leaves, contain bioactive compounds with the ability to create protective barriers on metal surfaces, contributing to a decrease in the corrosion rate of metallic compounds. Najem et al. [ref. 55] showed an inhibition rate of 90.13% for carbon steel in oil formation water, suggesting the physical adsorption of active components on the steel surface. Thus, it is reasonable to assume the promising use of these residues as efficient and environmentally sustainable corrosion inhibitors.

The extract from C. reticulata stem bark demonstrated significant cytotoxic activity against lung cancer (A549), breast (MCF7), and prostate (PC3) cells, with low IC₅₀ values, especially in MCF7 cells. A fraction rich in compounds such as scoparone (86), xanthyletin (87), lupeol (79), and plant sterols showed strong cytotoxic action and selectivity, minimally affecting normal cells. The results suggest a promising anticancer potential, possibly associated with synergistic effects between the isolated compounds, as exposed by Tahsin et al. [ref. 24].

Srimathi et al. [ref. 59] demonstrated that naringenin (104), a flavonoid isolated from C. reticulata peels, shows significant potential in neutralizing the toxic effects of N. naja cobra venom. In in vitro tests, naringenin (104) inhibited 51% of PLA₂ enzyme activity and reduced venom‐induced hemolytic activity by 59.8%. In in vivo experiments, performed in murine models, significant reductions in inflammatory processes, such as edema, were observed, in addition to protective effects on tissues, evidenced by histopathological analyses.

Castro et al. [ref. 18] demonstrated that the EO extracted from the fruit peels significantly inhibits the proliferation of non‐small cell lung cancer cells. The oil reduced cell growth in a dose‐dependent manner. The observed mechanisms included cell cycle arrest in the G₀/G₁ phase, reduction of membrane‐bound Ras protein, and induction of apoptosis. Furthermore, no signs of hepatic toxicity were identified.

The insecticidal activity of EOs against Thrips flavus was associated with their chemical composition. The EO from C. reticulata leaves, rich in monoterpenes, and from the peels, with a high content of D‐limonene (3), showed 100% pest control. Linalool (19) showed good toxicity and attractiveness, suggesting behavioral action. These results indicate that compounds such as D‐limonene (3) and linalool (19) are responsible for the efficacy of these oils, reinforcing their potential in natural pest control, narrates Pei et al. [ref. 60].

Future Perspectives

• Formulation of nanoparticles containing limonene or flavonoids from the peels for transdermal or oral application with controlled release;
• Potential application: prevention of chronic diseases through the modulation of signaling pathways such as NF‐κB, PI3K/Akt, and MAPK;
• Nutraceutical formulations with standardized extracts aiming at neuronal protection and clonal anti‐inflammatory activity;
• Use in medical surface coatings, mouthwashes, and natural preservatives through biofilm control;
• Use of agricultural waste (peels and leaves) in the formulation of products for organic agriculture (biopesticides);
• Incorporation into topical emulsions and anti‐acne products with a natural and sustainable appeal;
• Genetic modification of microorganisms for potentiation of C. reticulata Blanco bioactive compounds.

Registration of Patents for Citrus reticulata Blanco

The World Intellectual Property Organization (WIPO) is included in the global sharing of registered patents. WIPO data concerning the C. reticulata Blanco species comprises its use as food, insecticidal activity, anti‐inflammatory, and antioxidant activities (Table 2).

The C. reticulata species has been widely explored in various technological fronts, as evidenced by the patent survey that demonstrates its multifunctional potential. The identified applications range from the food industry to pharmaceutical, agricultural, and industrial sectors, highlighting the versatility of the compounds present in this species.

In the food sector, preparations for teas, liqueurs, wines, and flours enriched with flavoring additives stand out. Applications are also reported in food preservation processes, including compositions for freezing, defrosting, and chilling, as well as formulations for nonalcoholic beverages and dietary products with a focus on modifying nutritional properties, such as uric acid reduction.

In the health field, medicinal applications are numerous, including formulations with anticancer, anti‐inflammatory, hepatoprotective, antiulcerative, antimicrobial, and probiotic therapeutic activity. Patents also describe the use of the plant in the treatment of dermatological and sensory disorders, such as in the case of pulmonary embolism, as well as in specific medicinal preparations for cleaning, sterilization, and disinfection.

In phytotherapy, the use of C. reticulata in therapeutic baths is noteworthy, whereas in the field of plant biotechnology, its application in vegetative propagation techniques by tissue culture is observed. From an agricultural and environmental perspective, the species is applied as fertilizer and soil amendment, in addition to comprising formulations for biocides, repellents, pest attractants, and plant growth regulators, with emphasis on its insecticidal action.

In the field of chemistry and materials engineering, uses emerge in compositions of solid adsorbents and filtration aids, including in chromatography, as well as in processes for the preparation and activation of catalysts, with potential application in biodiesel production. The presence of compounds containing saccharide radicals also opens up space for investigations in fine chemistry and biotechnology. This set of applications reinforces the strategic value of C. reticulata as a source of technological innovation, with concrete possibilities for the development of new products and processes in the most diverse areas.

Conclusion

The different parts of the plant C. reticulata Blanco exhibit a wide range of biological properties, with particular emphasis on the fruit peels, where most secondary metabolites are concentrated. Among these compounds, flavonoids constitute the main nonvolatile components, whereas terpenes represent the predominant volatile compounds, both widely recognized for their multiple pharmacological activities.

The species C. reticulata stands out as a promising natural resource for the development of new therapeutic alternatives, especially in the face of the growing challenge of antimicrobial resistance to conventional treatments. In addition, it shows potential in combating oxidative stress, allergic reactions, and skin disorders associated with the action of free radicals. Its anti‐inflammatory properties are related to the modulation of cellular signaling and cell cycle regulators, further reinforcing its biotechnological relevance.

Future research should focus on elucidating the molecular mechanisms underlying the species’ antibiotic and antioxidant potential, as well as its possible role in modulation processes. Therefore, it is essential to explore its applications in improving the nutritional quality of foods, developing dietary products, controlling pests, and formulating natural fertilizers, always prioritizing safe and non‐toxic medicinal use.

Author Contributions

José Walber Gonçalves Castro: research, writing, formatting, chemical structure, and editing. Geane Gabriele de Oliveira Souza: research, writing, formatting, and editing. José Galberto Martins da Costa: conception of the idea and revision. Fabíola Fernandes Galvão Rodrigues: conception of the idea and revision.

Conflicts of Interest

The authors declare no conflicts of interest.

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