Nuclear factor erythroid 2-related factor 2 (Nrf2) inhibition revisited: advances and unmet challenges

BACKGROUND: Over the past decades, NRF2 has evolved from a redox/detox regulator to a central orchestrator of cellular stability, governing protein integrity, metabolism, immunity, and iron homeostasis, with roles in cancer, metabolic, inflammatory, and neurodegenerative diseases. It exhibits a "Taiji-like" duality: a cytoprotective "Yang phase" under stress versus a tumor-promoting "Yin phase" (featuring metabolic reprogramming and chemoresistance) upon aberrant activation. As a promising cancer target, specific NRF2 inhibitors remain largely in the preclinical stage, necessitating an integrated synthesis of its biological roles and translational potential. AIM OF REVIEW: This review systematically delineates the multifaceted biological functions of NRF2, with a focused emphasis on its context-dependent cancer-promoting effects. It not only integrates fragmented insights into NRF2's dualistic roles in cellular homeostasis and tumor progression but also highlights underexplored nuances within its regulatory network. Furthermore, it discusses potential NRF2 inhibition strategies, profiles investigational NRF2-targeting agents, and examines key therapeutic challenges that hinder the translation of these inhibitors into clinical practice. KEY SCIENTIFIC CONCEPTS OF REVIEW: We contextualize NRF2's dualism as a core barrier to its therapeutic targeting: while its cytoprotective functions are indispensable for physiological homeostasis, its overactivation fuels tumor progression. We further survey the landscape of preclinical NRF2 inhibitors, analyzing their mechanisms of action and limitations in specificity or efficacy. A central focus is placed on how resolving the paradox of NRF2's dual roles-through precision strategies that selectively abrogate its tumor-promoting Yin phase-could unlock its therapeutic potential in cancer. By bridging insights into NRF2's biological regulation with translational oncology and precision medicine frameworks, this review outlines a path to advance NRF2-targeted therapies.