Role of ferroptosis inhibitors in the management of diabetes

Abstract

Ferroptosis, the iron‐dependent, lipid peroxide‐mediated cell death, has garnered attention due to its critical involvement in crucial physiological and pathological cellular processes. Indeed, several studies have attributed its role in developing a range of disorders, including diabetes. As accumulating evidence further the understanding of ferroptotic mechanisms, the impact this specialized mode of cell death has on diabetic pathogenesis is still unclear. Several in vivo and in vitro studies have highlighted the association of ferroptosis with beta‐cell death and insulin resistance, supported by observations of marked alterations in ferroptotic markers in experimental diabetes models. The constant improvement in understanding ferroptosis in diabetes has demonstrated it as a potential therapeutic target in diabetic management. In this regard, ferroptosis inhibitors promise to rescue pancreatic beta‐cell function and alleviate diabetes and its complications. This review article elucidates the key ferroptotic pathways that mediate beta‐cell death in diabetes, and its complications. In particular, we share our insight into the cross talk between ferroptosis and other hallmark pathogenic mediators such as oxidative and endoplasmic reticulum stress regulators relevant to diabetes progression. Further, we extensively summarize the recent developments on the role of ferroptosis inhibitors and their therapeutic action in alleviating diabetes and its complications.

Theaflavin-3,3′-digallate alleviates glucolipotoxicity-induced insulin secretion dysfunction in pancreatic β-TC-6 cells and zebrafish via anti-ferroptotic mechanisms by activating SERCA2

“…Two major ER chaperones, BIP and CALR, play a variety of roles along with ER-localized DnaJ family members (ERdjs), SERCA2 or calnexin, including regulating protein folding, maintaining Ca 2+ and ATP homeostasis, and protecting cells against ER-derived oxidative stress [45,46]. Obesity-induced ER stress causes intercellular iron accumulation, which has been speculated to account for impaired insulin secretion and diabetes progression [47]. Genetic ablation or inhibition of PERK caused pancreatic damage in mice by stimulating type 1 interferon signalling [48].…”