The Analgesic Effects of Nrf2 Activators in Chemotherapy-Induced Neuropathic Pain: Evidence from Animal Studies and Consequences for Translation into Clinical Trials

Article type: Review Article

Keywords: chemotherapy-induced neuropathic pain, Nrf2, analgesic effects, review

Authors: Jimin Kim, Jeongmin Kim, Hee Kee Kim, Salahadin Abdi ⚬

Affiliations: University of the Incarnate Word School of Osteopathic Medicine, San Antonio, TX 78235, USA; jikim13@student.uiwtx.edu; Department of Epidemiology Concentration in Pharmacoepidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; jeongminhanakim@gmail.com; Department of Science, Southern Reformed College and Seminary, Houston, TX 77084, USA; Department of Pain Medicine, Division of Anesthesiology, Critical Care & Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

License: © 2026 by the authors. CC BY 4.0 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.

Article links: DOI: 10.3390/ijms27041748  |  PubMed: 41751884  |  PMC: PMC12940216

Relevance: Moderate: mentioned 3+ times in text

Full text: PDF (616 KB)

1. Introduction

Peripheral neuropathy is caused by damage to the nerves that constitute the peripheral nervous system and results in a condition with pain, stabbing, tingling, burning, weakness, and numbness in the peripheral tissues, especially the hands and feet. It can be triggered by cancer, traumatic injuries, infections, metabolic diseases (e.g., diabetes), stroke, herpes zoster, and neurotoxic drugs (e.g., chemotherapeutic drugs) [ref. 1]. Neuropathic pain arises from lesions or dysfunctions within the somatosensory nervous system with pain, including allodynia, hyperalgesia, or numbness [ref. 2]. It is treated with antidepressants, anticonvulsants, topical analgesics, and opioids, which results in a modest analgesic effect [ref. 1].

Chemotherapy-induced neuropathic pain (CINP) can be caused by several chemotherapeutic drugs, including (1) platinum drugs (cisplatin and oxaliplatin), (2) vinca alkaloids (vincristine, vinblastine, and vinorelbine), (3) anti-microtubule agents (taxanes, including paclitaxel, and docetaxel), (4) proteasome inhibitors (bortezomib), and (5) immunomodulatory agents (thalidomide and lenalidomide) [ref. 3]. CINP stands as a major, enduring complication of chemotherapy, impacting an estimated 30–40% of patients annually [ref. 4]. This serious adverse effect can lead to premature cessation of chemotherapy or dose reductions, ultimately compromising treatment efficacy and patient survival rates [ref. 5]. The intensity of CINP is influenced by the duration of chemotherapeutic drugs [ref. 6]. Despite its significant clinical impact, the treatment of CINP represents a considerable medical challenge, primarily stemming from the absence of agents recommended for its prevention and management within the American Society for Clinical Oncology clinical practice guidelines [ref. 7]. The patho-mechanisms of CINP are not completely understood; however, oxidative stress has been reported as one of its patho-mechanisms, which means nuclear factor erythroid 2-related factor 2 (Nrf2) activators show analgesic effects in CINP. The previous two review articles were reported on Nrf2 in preclinical models of chronic pain [ref. 8,ref. 9]. Therefore, the purposes of our review article were to summarize the analgesic effects of Nrf2 activators on preclinical and clinical studies with CINP and patho-mechanisms of Nrf2.

1.1. Patho-Mechanisms of CINP

Platinum drugs and proteasome inhibitors can damage sensory nerves [ref. 10]. In addition, others, including vinca alkaloids and anti-microtubule agents, can damage both sensory and motor nerves [ref. 10]. They destroyed peripheral nervous tissues like dorsal root ganglia (DRG), skin nerve terminals, and primary sensory neurons [ref. 10]. The mechanisms of CINP include: (1) decreases of the number of intraepidermal nerve fibers in skin nerve terminals; (2) increases of abnormal function of Aβ, Aδ, and C fibers by vincristine; (3) the slowing nerve conduction velocity by cisplatin, paclitaxel, and bortezomib; (4) binding of paclitaxel and oxaliplatin to the DRG; (5) alteration of the function of voltage-gated sodium channels by oxaliplatin; (6) damage of mitochondria by paclitaxel, vincristine, cisplatin, and bortezomib; (7) release of intracellular calcium; (8) increases of α2δ1 subunits of voltage-gated calcium channels in the dorsal horn and DRG; (9) upregulation of transient receptor potential (TRP) vanilloid 1, TRPA1, TRPM8, and TRPV4 in the DRG by cisplatin, oxaliplatin, and paclitaxel; (10) increases of reactive oxygen species in the DRG by cisplatin, oxaliplatin, and paclitaxel; (11) increases of spontaneous activity and after-discharges in the dorsal horn by paclitaxel; and (12) induction of glutamate excitotoxicity [ref. 3] (Figure 1).

In addition, chemotherapeutic agents can affect immune cells, including macrophages, epidermal Langerhans cells, and glial cells. They produce (1) increases in oxidative stress, (2) increases in the number of Langerhans cells in the skin, (3) induction of matrix metalloproteinases in DRG, (4) activation of macrophages in DRG, and (5) induction of inflammatory cytokines [ref. 3]. Oxidative stress is one of the underlying patho-mechanisms of CINP [ref. 9]. Furthermore, Nrf2 (nuclear factor erythroid 2-related factor 2) is a critical regulator of oxidative stress and decreases oxidative stress [ref. 11] (Figure 1). Thus, the Nrf2 activator contributed to the analgesic effects of CINP [ref. 11].

1.2. Action of Nrf2 Activators in CINP

Characterized by an imbalance, oxidative stress involves an excess of free radicals—reactive oxygen species (e.g., superoxide anions and hydrogen peroxide) and reactive nitrogen species (nitric oxide)—relative to the available low levels of antioxidants, including superoxide dismutase (SOD), nitric oxide synthase, glutathione peroxidase (GPX), vitamin C, and vitamin E [ref. 12].

In CINP, chemotherapeutic agents, including paclitaxel, induced free radical production and mitochondrial dysfunction in the peripheral nerve [ref. 13]. Free radicals are produced by enzymes in nervous cells and immune cells, including macrophage, neutrophil, lymphocyte, and dendritic cells [ref. 14]. In addition, oxidative stress produced proinflammatory inducers, which include pro-inflammatory cytokines and adhesion molecules, by the activation of nuclear factor kappa B (NF-κB) [ref. 15]. By initiating the degradation of IκB, a protein that normally inhibits NF-κB, leading to the translocation of NF-κB (p50 and p65 subunit) to the nucleus and then activation of proinflammatory responses, oxidative stress can lead to the activation of NF-κB, which induces PINP [ref. 11].

Nrf2 is produced by the NFE2L2 gene. Nrf2 contains a bZip domain at the C-terminus that is responsible for the formation of heterodimers with other bZip proteins, such as small muscle aponeurosis fibromatosis (MAF) [ref. 16]. These heterodimers are the regulators of human genes, including the antioxidant response element (ARE), which resembles the NFE2-binding motif [ref. 16]. In neuropathic pain conditions, Nrf2 is released from Keap1 and translocates to the nucleus, where it heterodimerizes with MAF proteins. The complex Nrf2–MAF binds to ARE, initiating the transcriptions of several cytoprotective genes, such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase1 (NQO1), SOD, glutathione cysteine ligase, glutathione S-transferases, and catalase, which induce antioxidant defense [ref. 17]. Nrf2 activators decreased oxidative stress by inhibiting the translocation of NF-κB to the nucleus, which produces analgesic effects in CINP (Figure 2). We conducted this review as a State-of-the Art Narrow Reviews.

2. Results and Discussion

2.1. Analgesic Effects of Nrf2 Activators in CINP: Preclinical (Animal) Studies

2.1.1. Paclitaxel-Induced Neuropathic Pain (PINP) Model

The collection of studies explored various therapeutic approaches to alleviate CINP, a common and debilitating side effect of chemotherapy drugs like paclitaxel. Several studies indicate that activating Nrf2 plays a significant role in mitigating PINP (Table 1).

In the PINP rat, electroacupuncture at Neiguan and Jianshi acupoints reduced mechanical and thermal hypersensitivity by modulating Nrf2-ARE and increasing SOD in the DRG [ref. 18]. Similarly, combined administration of tempol (SOD mimetic), vitamin C, and GKT137831 (NADPH oxidase inhibitor) also restored Nrf2-ARE signaling pathway and then attenuated mechanical and thermal hypersensitivity [ref. 18].

Oltipraz, an Nrf2 activator, reduced mechanical allodynia and significantly alleviated PINP after repeated oltipraz injections by increasing Nrf2 in the spinal cord [ref. 19]. Furthermore, early oltipraz treatment delayed the onset of PINP, but it did not prevent the pain from developing [ref. 19].

Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, alleviated established PINP and delayed the onset of neuropathic pain by increasing Nrf2 expression [ref. 20]. Furthermore, these analgesic effects were reversed by both PPARγ antagonist and Nrf2 inhibitor, confirming the roles of PPARγ and Nrf2 in this process [ref. 20].

Hydrogen-rich water (HRW) was administered systemically to reduce mechanical and thermal allodynia in PINP and improve memory and alleviate anxiety- and depressive-like behaviors by modulating the Nrf2 pathway [ref. 21].

Pristimerin, one of the triterpenes, showed promise in promoting Nrf2 activation, a key antioxidant defense, and in inhibiting monoacylglycerol lipase activity, preventing the development of PINP in mice [ref. 22]. Similarly, the combination of cannabidiol (CBD) and tetrahydrocannabivarin (THCV) demonstrated neuroprotective effects by modulating Nrf2 in DRG and improving behavioral outcomes [ref. 23].

Daidzein (DZ), a soy isoflavone, activated the Nrf2 pathway, leading to enhanced antioxidant enzyme expression and diminished neuronal apoptosis in CINP models [ref. 24]. It also alleviated pain hypersensitivity, reduced TRPV1 and P2Y receptor expression, and activated Nrf2-related antioxidant pathways, while also decreasing neuroinflammation and apoptosis [ref. 24]. The Commiphora myrrha (CM) extract provided protection against paclitaxel-induced hyperalgesia and allodynia, showing similar benefits via peripheral TRPV1 inhibition and the restoration of Nrf2 [ref. 24].

Other studies demonstrated that bardoxolone methyl (BM), an Nrf2 activator, provided analgesic effects by restoring Nrf2 expression, reducing inflammation, and improving mitochondrial function in DRG neurons [ref. 9]. In a related study, resolvin D1 (RvD1), a lipid mediator, alleviated PINP by regulating immune responses through N-formyl peptide receptor 2 and IL-10, activating Nrf2-HO1 signaling pathways in DRG neurons, and reducing oxidative stress and neuronal damage [ref. 25].

A combination therapy of cobalt protoporphyrin IX (CoPP) with HRW demonstrated enhanced efficacy in treating PINP, improving both pain and emotional disorders by reducing inflammation and activating the HO-1/Nrf2 axis [ref. 26].

Finally, caffeic acid phenethyl ester (CAPE), a phenolic compound, alleviated PINP by inhibiting β-catenin, an important Wnt signaling protein; reducing the expression of inflammatory markers such as matrix metalloproteinase 2; and promoting Nrf2 activation [ref. 27].

They underscore that activating Nrf2 could be a therapeutic strategy to prevent and alleviate PINP by modulating oxidative stress, inflammation, and cellular damage. Thus, Nrf2 represents a promising target for future therapies aimed at treating PINP.

2.1.2. Oxaliplatin-Induced Neuropathic Pain (OINP) Model

Oxaliplatin, a widely used chemotherapeutic agent, frequently induces peripheral neuropathy characterized by pain and sensory dysfunction, largely driven by oxidative stress and inflammation. Through several studies, various strategies targeting the antioxidant pathway—particularly involving Nrf2—demonstrated protective or therapeutic effects against OINP. Nrf2 plays a pivotal role in mitigating this neurotoxicity, as highlighted by multiple studies (Table 2).

Inhibition of microRNA-155 restored Nrf2-ARE signaling and reduced oxidative markers and pain behaviors [ref. 29]. Natural compounds like puerarin, resveratrol, and curcumin enhanced Nrf2 activity and its downstream targets such as glutathione peroxidase 4 (GPX4), HO-1, and NQO1, mitigating oxidative stress and inflammation while improving pain thresholds and motor coordination [ref. 29,ref. 30,ref. 31]. Puerarin and curcumin enhanced Nrf2/GPX4 signaling, suppressed inflammatory responses via the NLRP3 inflammasome, and alleviated pain symptoms [ref. 31,ref. 32]. Resveratrol further amplified Nrf2 activity, boosting the expression of HO-1, while attenuating neuroinflammation and behavioral hypersensitivity [ref. 30]. Additionally, bone marrow-derived mesenchymal stem cells reversed OINP by upregulating Nrf2 and antioxidant enzymes like SOD, along with anti-inflammatory cytokines IL-10 and TGF-β [ref. 33].

Collectively, the results emphasize Nrf2’s critical role in regulating oxidative stress and neuroinflammation in OINP and support antioxidant-focused therapies as promising approaches for managing chemotherapy-induced peripheral neuropathic pain.

2.1.3. Vincristine-Induced Neuropathic Pain (VINP) Model

Vincristine, a common chemotherapeutic agent, induces neuropathic pain through mechanisms such as oxidative stress and inflammation. In studies investigating therapeutic options, compounds like levo-corydalmine (l-CDL), mitoquinone, and ajugarin-I show potential for alleviating VINP, as shown in Table 3 [ref. 34,ref. 35,ref. 36]. l-CDL activates the Nrf2, thereby reducing neuroinflammation and preventing nerve damage [ref. 34]. Mitoquinone, a mitochondrial-targeted antioxidant, improves VINP by reducing oxidative stress, restoring mitochondrial function, and protecting against neuronal apoptosis [ref. 35]. Ajugarin-I, derived from Ajuga bracteosa, mitigates neuropathy through its antioxidant and anti-inflammatory properties by regulating Nrf2/NF-κB and Bcl-2 signaling pathways [ref. 36]. These findings highlight Nrf2 activation as a common therapeutic target for preventing vincristine-induced neuropathy, reducing oxidative stress, and enhancing neuroprotection. This activation of Nrf2 helps in preventing neuronal damage, improving mitochondrial function, and alleviating pain, making it a potential therapeutic target for VINP.

2.2. Clinically Available Nrf2 Activators

The identification of effective Nrf2 activators is a major research focus for numerous diseases, including CINP. These compounds can be broadly classified into natural compounds (phytochemicals) and synthetic compounds, many of which have been studied in preclinical CINP models, with some progressing to clinical trials for other indications. In clinical studies in Table 4, curcumin showed significant efficacy in reducing vincristine-induced neuropathy in pediatric lymphoblastic leukemia patients, while the combination of alpha-lipoic acid and ipidacrin hydrochloride improved axonal function, preventing motor neuropathy induced by paclitaxel in breast cancer patients [ref. 37,ref. 38]. Both compounds, possessing Nrf2 activation, represent potential protective agents against neurotoxicity caused by different chemotherapy drugs.

In detail, the authors indicated that the prevalence of vincristine-induced peripheral neuropathy was substantially lower in the curcumin-treated group compared to the placebo group, as confirmed by both nerve conduction studies and needle electromyography assessments. Furthermore, curcumin demonstrated a protective effect against motor and sensory nerve damage, with a significant reduction in motor nerve abnormalities [ref. 35]. Natural curcumin and curcuminoids like monocarbonyl analogues produce antitumor actions acting on the following nuclear targets, including NF-κB, STAT3, topoisomerase IIα, and PARP. In addition, they influenced HIF-1α and then blocked angiogenesis. Furthermore, they disrupted tumor cell energy metabolism by inhibiting key glycolytic enzymes and reducing anaerobic energy production [ref. 39].

In breast cancer patients (stage II–IV) treated with paclitaxel with doxorubicin or epirubicin, alpha-lipoic acid, and ipidacrin hydrochloride tendency toward axonal damage and mild myelinopathy and significantly increased M-response rates of motor nerves after 6 cycles of polychemotherapy with paclitaxel [ref. 36].

Given its strong antioxidant, curcumin and alpha-lipoic acid may serve as a promising adjunct therapy for mitigating CINP.

2.2.1. Natural Nrf2 Activators (Phytochemicals)

These compounds are derived from plants and are often found in diets. They are generally perceived to have lower toxicity owing to their natural origin and dietary presence. They typically activate Nrf2 by interacting with specific cysteine residues on Keap1, leading to Nrf2 release and nuclear translocation. However, high doses, specific formulations or interactions with concurrent medications can still lead to adverse effects. In Table 4, natural Nrf2 activators were shown, including sulforaphane, curcumin, resveratrol, quercetin, alpha-lipoic acid, oltipraz, and berberine (Table 4).

2.2.2. Synthetic Nrf2 Activators

These compounds are designed and synthesized to specifically target and activate the Nrf2 pathway, often by disrupting the Keap1-Nrf2 interaction. These are generally more potent and selective, necessitating rigorous safety evaluation given their pharmaceutical nature. In Table 4, synthetic Nrf2 activators were shown, including dimethyl fumarate (DMF), monomethyl fumarate, omaveloxolone, and bardoxolone methyl (BM). Among them, DMF and omaveloxolone have approval from the FDA for multiple sclerosis and Friedreich’s ataxia, respectively, which means they have a well-characterized safety profile for chronic neurological conditions [ref. 40,ref. 41]. Therefore, they may be highly attractive candidates for CINP by conducting small pilot studies or an off-label study.

2.2.3. Considerations in Nrf2 CINP Clinical Trials

There are several considerations in clinical trials, including oncological priority, the complexity of CINP, study design challenges, and safety in cancer patients. For the oncological priority, the primary focus in oncology remains cancer treatment, and interventions for side effects must not compromise anti-cancer efficacy. Nrf2 activation can sometimes confer chemoresistance to cancer cells, which is a major concern. The complexity of CINP with varied etiologies depends on chemotherapy drug. Study design is challenging due to the variability in chemotherapy regimens and outcome measures. In addition, safety in cancer patients due to their multiple comorbidities.

2.3. Limitations

This review is subject to several limitations. First, the limited number of studies, particularly clinical trials, prevents definitive confirmation of the efficacy of Nrf2 activators for neuropathic pain. Second, it remains unclear whether Nrf2 activators are directly involved in the underlying mechanisms of chemotherapy-induced neuropathic pain. Finally, the use of Nrf2 activators in oncology is further complicated by the lack of clarity regarding their potential anticancer effects.

2.4. Future Prospects

Future research efforts should focus on overcoming the current limitations to advance Nrf2 activators for clinical use. First, there is an urgent need for well-designed, dedicated clinical trials to establish the efficacy and safety of Nrf2 activators in human patients with chemotherapy-induced neuropathic pain. Second, mechanistic studies are required to clarify Nrf2’s precise role in the initiation versus the chronic maintenance of CINP pathways. Finally, investigations must prioritize clarifying the interaction between Nrf2 activators and standard chemotherapy regimens to ensure these compounds do not compromise anticancer efficacy, potentially through developing localized or tumor-specific delivery methods.

3. Materials and Methods

We conducted a reproducible, English-only systematic search of MEDLINE (PubMed) for all relevant studies published since its inception until the search execution date of 1 December 2024. The search focused on combining terms for Nrf2, chemotherapy, and neuropathic pain, with the inclusion criteria being ((Nrf2) AND (chemotherapy) AND (neuropathic pain)) from 1966 to 2024, sorted by publication date. We strictly limited the results to Animal and clinical Studies. The subsequent screening, performed by two independent authors, enforced stringent exclusion criteria against review articles and non-chemotherapy-induced neuropathic pain models, including chronic constriction injury, diabetic neuropathy, nerve ligation, alcohol, spinal cord injury, and visceral injury, to guarantee topic specificity. The search strategy is shown in Figure 3.

4. Conclusions

Paclitaxel, oxaliplatin, and vincristine, potent chemotherapeutic agents, lead to the development of CINP, which significantly impacts patients’ quality of life. Oxidative stress and inflammation play central roles in CINP. Targeting pathways, such as Nrf2, which regulate antioxidant responses and inflammatory responses, has shown promising therapeutic potential in attenuating these painful conditions. In CINP studies, the Nrf2 activators, including electroacupuncture, tempol, vitamin C and GKT137831, oltipraz, rosiglitazone, hydrogen-rich water, pristimerin, cannabidiol and tetrahydrocannabivarin, daidzein, Commiphora myrrha extract, resolving D1, bardoxolone methyl, caffeic acid phenethyl ester, miR-155 inhibitor, puerarin, resveratrol, curcumin, Levo-corydalmine, mitoquinone, and ajugarin-I, produced analgesic effects in animals. In clinical studies, curcumin and alpha-lipoic acid demonstrated significant efficacy in reducing CINP. Furthermore, modulation of inflammatory cytokines and apoptotic pathways may enhance neuroprotection, providing a potential avenue for creating effective therapies for CINP. Targeting the Nrf2 pathway offers a strategy for mitigating CINP, thus improving patient outcomes and quality of life during cancer treatment.

Given the data, Nrf2 activators may produce analgesic effects in CINP by decreasing oxidative stress and neuroinflammation as well as increasing neuroprotection. In addition, their difficulties may be low bioavailability and the possibility of cancer cell proliferation (Figure 4). Improving the bioavailability of Nrf2 activators (e.g., curcumin, sulforaphane, and resveratrol) focuses on overcoming their poor absorption, rapid metabolism, and low water solubility. Key strategies include using nano-formulations, liposomes, and self-microemulsifying drug delivery systems to increase plasma concentrations, as seen with significant, often manifold, increases in bioavailability in studies [ref. 58,ref. 59,ref. 60].

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