Mechanisms and therapeutic strategies targeting the reversible phosphorylation-endoplasmic reticulum stress network in diabetic cardiomyopathy.

The pathological progression of diabetic cardiomyopathy (DCM) involves multiple interconnected mechanisms, including metabolic reprogramming, oxidative stress, Ca2+ dysregulation, and programmed cell death. Recent studies have shown that reversible protein phosphorylation, endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are not independent events, but rather form an interactive network through the dynamic balance mediated by kinases and phosphatases, thereby coordinating cardiomyocyte fate. This review focuses on the reciprocal regulation of reversible phosphorylation and ER stress in diabetic cardiomyopathy and further discusses the role of mitochondria-associated membranes (MAMs) in coupling Ca2+ transfer, oxidative stress, mitochondrial dysfunction, and cell death signaling. Additionally, this review summarizes recent advances in natural bioactive compounds and kinase/phosphatase modulators for targeting these pathological processes, providing insights for mechanistic studies and the optimization of therapeutic strategies for diabetic cardiomyopathy.