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

TL;DR

This paper reviews how post-translational modifications affect mTOR signaling and cell death in cardiovascular diseases, offering insights into new treatment strategies.

Contribution

The paper provides a systematic review of PTM-mediated regulation of mTOR signaling in cardiovascular pathophysiology and emerging therapeutic strategies.

Findings

PTMs like phosphorylation and ubiquitination regulate mTOR activity and influence cell death pathways in CVDs.

Targeting PTMs or the mTOR axis with inhibitors and modulators shows therapeutic potential in preclinical and clinical settings.

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.

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