Progress in biophysics and molecular biologyJun 4, 2026

How protein balance controls cell death through the p62-Keap1-Nrf2 antioxidant system

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 8, 2026

Abstract

Ferroptosis may emerge from a dynamic balance involving proteostasis integrity and redox buffering capacity.

Ferroptosis is driven by excessive lipid peroxidation and is linked to various pathological conditions.
p62 is a protein that plays a role in maintaining cellular health by managing protein quality and participating in stress responses.
Changes in p62 levels occur during cellular stress and may affect the Keap1-Nrf2 signaling pathway, connecting protein balance to redox regulation.
The relationship between the p62-Keap1-Nrf2 pathway and ferroptosis is complex and not fully understood across different experimental systems.
The review highlights that the p62-Keap1-Nrf2 axis functions more as a regulatory system rather than a direct executor of ferroptosis.

Simplified

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.

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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

How protein balance controls cell death through the p62-Keap1-Nrf2 antioxidant system

Abstract

Full Text

Funding

Competing interests

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