NRF2 Dysregulation and Its Implications in Renal Cell Carcinoma

Renal cell carcinoma (RCC) comprises molecularly distinct subtypes with limited treatment options for metastatic disease.The NRF2 pathway, a master regulator of cellular antioxidant responses, exhibits frequent dysregulation across RCC subtypes through distinct mechanisms.Clear cell RCC predominantly demonstrates NRF2 activation via epigenetic KEAP1 silencing and SQSTM1 amplification, while papillary RCC shows genetic mutations in core NRF2-pathway genes and metabolic NRF2 activation through fumarate accumulation in FH-deficient tumors.Chronic NRF2 hyperactivation fundamentally alters RCC biology by promoting tumor cell proliferation, facilitating epithelial-mesenchymal transition that drives metastatic dissemination, and modulating the immune microenvironment to enable immune evasion and checkpoint inhibitor resistance.Preclinical and clinical studies consistently demonstrate associations between NRF2 activation and poor patient outcomes, including reduced overall survival, increased metastatic potential, and therapeutic resistance to tyrosine kinase inhibitors and immunotherapy.These findings establish NRF2 as both a prognostic biomarker and potential therapeutic target in RCC.The development of selective NRF2 inhibitors represents a promising therapeutic strategy that could sensitize tumors to existing treatments, overcome drug resistance, and improve patient outcomes through combination approaches while preserving normal tissue protection.