Post-translational modifications orchestrate mTOR-driven cell death in cardiovascular disease.

Abstract

The mechanistic target of rapamycin (mTOR) signaling pathway is a central regulator of cellular physiology, modulating processes such as metabolism, protein synthesis, growth, and various forms of cell death. Increasing evidence has revealed that dysregulation of mTOR activity, often triggered or exacerbated by aberrant post-translational modifications (PTMs), contributes to the onset and progression of cardiovascular diseases (CVDs), including atherosclerosis, myocardial infarction, heart failure, and ischemia-reperfusion injury. PTMs such as phosphorylation, ubiquitination, SUMOylation, acetylation, and glycosylation alter mTOR's upstream regulators and downstream effectors, influencing the balance between apoptosis, autophagy, pyroptosis, and ferroptosis. These regulatory mechanisms provide a molecular basis for cell fate decisions during cardiovascular stress and injury. In this review, we systematically summarize recent advances in the understanding of PTM-mediated control of mTOR signaling, with a focus on cardiovascular pathophysiology. We also highlight emerging therapeutic strategies that target PTMs or the mTOR axis, including mTOR inhibitors, AMPK activators, proteasome blockers, and SUMOylation modulators, all of which show promise in preclinical or clinical settings. Understanding how PTMs fine-tune mTOR activity and cell death may pave the way for novel, targeted interventions in cardiovascular medicine and offer potential avenues for the development of precision therapies.