Targeting PERK signaling: mechanisms and roles in myocardial protection

Myocardial injury-related diseases represent a critical issue in the field of cardiovascular medicine, characterized not only by significant clinical hazards and complex pathological mechanisms but also by severe long-term prognostic implications for patients. In the pathophysiological processes mediated by endoplasmic reticulum stress (ERS), PERK, as a core signaling branch of the unfolded protein response (UPR), has been demonstrated to play a widespread role in the onset and progression of myocardial injury. Additionally, PERK is highly enriched in the mitochondria-associated endoplasmic reticulum membrane (MAMs), a subcellular structural platform, where it exerts multidimensional effects in myocardial protection by integrating ERS signals with mitochondrial function regulation. However, previous intervention strategies have primarily focused on inhibiting PERK activity to mitigate ERS-associated cellular damage. With deeper exploration of the complexity of the PERK signaling network, it has been revealed that unresolved chronic ERS and persistent PERK activation can severely impair cell survival. Conversely, moderate PERK stimulation may promote cardiac adaptive responses and exert cardioprotective effects, suggesting that bidirectional regulation of PERK could offer a novel perspective for the treatment of myocardial injury-related diseases. This review systematically summarizes the latest research advances in the PERK signaling pathway and summarizes the applications of PERK activators and inhibitors in myocardial protection, providing novel potential therapeutic strategies for diseases related to myocardial injury.