Impaired endoplasmic reticulum (ER) Ca 2+ homeostasis contributes to β ‐cell dysfunction under diabetic stressors such as methylglyoxal (MGX), a reactive byproduct that induces oxidative protein modifications and advanced glycation end‐products. The calcium pump sarco/endoplasmic reticulum Ca 2+ ‐ATPase (SERCA), essential for ER Ca 2+ regulation, is inhibited by MGX‐mediated carbonylation and thiol oxidation. Pharmacological SERCA activation has emerged as a promising strategy to restore ER Ca 2+ balance, but whether protection results from direct allosteric modulation, indirect antioxidant effects, or both has remained unclear. Herein, it is shown that novel, potent synthetic activators directly stimulate SERCA and restore its activity following MGX‐induced inhibition. While some compounds display antioxidant activity, recovery of SERCA function correlated with activation potency rather than radical scavenging or lipid peroxidation inhibition. It is demonstrated for the first time that direct SERCA activation alone is sufficient to significantly reverse oxidative damage, revealing a mechanistically distinct therapeutic approach to preserve ER Ca 2+ homeostasis in diabetes.
Micháliková et al. (2025) studied this question.