TRPA1 activation prompts lysosome-mediated Nrf2 degradation enhancing the killing of colorectal cancer cells

Abstract Redox homeostasis is crucial for cancer cell survival and resistance to therapy. The transcription factor NRF2, a master regulator of antioxidant and metabolic genes, is often upregulated in tumors to mitigate oxidative stress. Although NRF2 stability is canonically governed by KEAP1–CUL3–proteasome degradation, emerging evidence implicates lysosomal and autophagic pathways in non-canonical NRF2 turnover. The mechanisms by which these alternative pathways are engaged during chronic oxidative signaling remain unclear. We investigated whether sustained activation of the redox-sensitive ion channel TRPA1