KEAP1-mediated regulation of ferroptosis: from canonical and non-canonical mechanisms to therapeutic targeting

Kelch-like ECH-associated protein 1 (KEAP1) is a substrate adaptor of the Cullin-RING E3 ubiquitin ligase complex (CRL3) and a critical regulator of cellular redox homeostasis through controlling nuclear factor erythroid 2-related factor 2 (NRF2) stability. Dysregulation of KEAP1-NRF2 signaling contributes to tumor progression, metabolic adaptation, therapeutic resistance, and ferroptosis evasion. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising strategy for targeting therapy-resistant cancers. The canonical KEAP1-NRF2 pathway regulates ferroptosis mainly through antioxidant defense systems, including the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) and the ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10) pathways. Recent studies have revealed that KEAP1 activity is finely regulated by diverse upstream mechanisms, including protein interactions, non-coding RNAs, epigenetic modifications, metabolic signaling, and post-translational modifications. These regulatory networks modulate KEAP1 function and subsequently influence NRF2 activation, redox homeostasis, and ferroptosis susceptibility. This review summarizes the canonical and non-canonical regulatory mechanisms of KEAP1 in ferroptosis, highlighting how multilayered regulation of the KEAP1-NRF2 axis contributes to tumor adaptation, therapeutic resistance, and ferroptosis-based interventions. We further discuss the potential of KEAP1-associated regulatory mechanisms as biomarkers and therapeutic targets for precision cancer therapy.