Small‐Molecule Sarco/Endoplasmic Reticulum Ca ²⁺ ‐ATPase Activators Reverse Methylglyoxal‐Induced Inhibition through Nonantioxidant Mechanisms

Impaired endoplasmic reticulum (ER) Ca²⁺ 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 Ca²⁺-ATPase (SERCA), essential for ER Ca²⁺ regulation, is inhibited by MGX-mediated carbonylation and thiol oxidation. Pharmacological SERCA activation has emerged as a promising strategy to restore ER Ca²⁺ 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 Ca²⁺ homeostasis in diabetes.