Proteostasis-driven redox adaptation in ferroptosis: the p62-Keap1-Nrf2 axis

Ferroptosis is an iron dependent form of regulated cell death driven by excessive lipid peroxidation and implicated in numerous pathological conditions. While current research has largely focused on lipid metabolism and antioxidant systems, the contribution of upstream disturbances in protein homeostasis remains insufficiently integrated into ferroptosis frameworks. p62 is a multifunctional adaptor protein involved in ubiquitin mediated proteostasis, selective autophagy, and redox signaling. Emerging evidence indicates that alterations in p62 turnover occur under cellular stress conditions associated with ferroptosis and influence the Keap1-Nrf2 (NFE2L2) signaling axis, thereby linking proteostasis imbalance to redox regulation. However, the functional implications of this interaction remain fragmented across experimental systems. In this review, we integrate recent findings on the p62-Keap1-Nrf2 pathway in ferroptosis related processes, emphasizing its roles in redox buffering, autophagic flux, and cellular stress adaptation. Rather than directly executing ferroptosis, the p62-Keap1-Nrf2 axis is better understood as a regulatory system linking proteostasis to redox balance. We propose a conceptual framework in which ferroptosis emerges from a dynamic balance between proteostasis integrity, redox buffering capacity, iron metabolism, and lipid oxidative stress.