From Metabolic Memory to Ferroptotic Susceptibility: A Critical Review of Epigenetic Regulation and Ferroptosis in Diabetic Complications

Abstract

Background:

The clinical phenomenon of metabolic memory, in which diabetic complications may progress despite later glycemic improvement, lacks a complete explanation. Persistent oxidative stress, advanced glycation, mitochondrial dysfunction, and epigenetic remodeling are established contributors, but how these processes intersect with regulated cell death programs is still unresolved.

Main Body:

This review proposes and critically appraises the hypothesis that epigenetic dysregulation increases the susceptibility of diabetic tissues to ferroptosis. We employ the term “epigenetic-ferroptosis link” as an operational term denoting a potential mechanistic connection between hyperglycemia-associated chromatin/RNA-regulatory alterations and shifts in ferroptosis vulnerability. A key methodological tenet of our analysis is the clear demarcation between direct evidence from diabetic models and supportive mechanistic insights drawn from other pathological contexts, ensuring a rigorous assessment of the hypothesis against the available data.

Conclusion:

Ferroptosis is one execution pathway among several that can contribute to diabetic tissue injury. This framing highlights the critical importance of organ- and cell-type specificity, the experimental rigor required to conclusively demonstrate ferroptosis involvement, the inherent limitations of extracellular-vesicle biomarkers and epigenetic-editing approaches, and the validation steps that remain necessary before any clinical translation can be contemplated. Antioxid. Redox Signal. 00, 000–000.