Platelet Autophagy as a Druggable Intracellular Pathway: Therapeutic Opportunities in Thromboinflammatory Diseases.

Platelet hyperreactivity is a central driver of thromboinflammatory diseases, including ischemic stroke, cardiovascular disorders, and autoimmune conditions. Current antiplatelet therapies primarily target surface receptors or coagulation pathways and are frequently limited by drug resistance, bleeding risk, and inadequate control of metabolically or inflammation-driven platelet dysfunction. Emerging evidence reveals that platelets possess a fully functional autophagic machinery that critically regulates mitochondrial quality, redox balance, granule secretion, cytoskeletal remodeling, and activation thresholds. This intracellular pathway represents a previously underrecognized but highly druggable regulatory axis in platelet biology. In this review, we examine the molecular framework governing autophagy in platelets, with emphasis on mTOR, AMPK, PI3K/AKT, and mitophagy signaling networks, and discuss how basal and activation-induced autophagy determine thrombotic behavior under physiological and pathological conditions. We then integrate clinical and preclinical evidence demonstrating how dysregulated platelet autophagy contributes to thrombotic risk in ischemic stroke, cardiovascular disease, metabolic disorders, and autoimmune diseases. Importantly, we highlight how pharmacological agents, including mTOR inhibitors, AMPK activators, natural autophagy enhancers, and lysosomal inhibitors, modulate platelet function through autophagy-dependent mechanisms. These findings position platelet autophagy as a promising intracellular therapeutic target that complements conventional antiplatelet strategies. We further discuss the translational challenges of autophagy-targeted therapy, including context dependency, lack of platelet-specific modulators, delivery strategies, and the need for reliable biomarkers to guide personalized intervention. By framing platelet autophagy as a druggable pathway rather than a biological curiosity, this review outlines a precision-targeted therapeutic framework for managing thromboinflammatory diseases through intracellular modulation of platelet behavior.