Tipping the balance: NRF2’s dual role in ferroptotic fate

The NRF2 pathway has emerged as a central regulator of cellular redox homeostasis, coordinating the expression of a broad array of genes that protect cells from oxidative and electrophilic stress. In the context of cancer, NRF2 has been recognized as a key driver of chemoresistance, as its sustained activation enhances antioxidant defenses, detoxification pathways, and metabolic adaptation, thereby promoting tumor cell survival under therapeutic stress. Beyond its canonical role in redox regulation, NRF2 also orchestrates the expression of multiple genes involved in ferroptosis, a non-apoptotic, iron-dependent form of cell death that has recently gained attention as a promising strategy to overcome drug resistance. Mechanistically, NRF2 modulates ferroptosis through several interconnected pathways, including the regulation of glutathione biosynthesis, lipid metabolism, and iron homeostasis, yet its impact is highly context-dependent and can vary according to cell type and metabolic state. In this review, we provide an overview of the interplay between NRF2 and ferroptosis, tracing the historical development of this network and highlighting the pivotal roles of specific NRF2 targets in controlling ferroptotic susceptibility. Finally, we discuss how targeted modulation of NRF2 may influence ferroptosis, offering a potential avenue for the design of innovative therapies aimed at selectively eradicating resistant tumors.