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

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.

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.

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. 45, 534-554.