Platelets promote acute liver injury via extracellular vesicles-mediated Aldolase A

Abstract Platelets have emerged as active regulators of acute liver injury (ALI), yet the molecular mechanisms underlying their pathogenic functions remain poorly defined. Here, we demonstrate that platelets exacerbate liver injury by metabolically reprogramming Kupffer cells (KCs). We show that platelets are actively recruited to the injured liver and communicate with KCs through extracellular vesicles (EVs), which deliver the glycolytic enzyme aldolase A (ALDOA) into recipient cells. This EV-mediated transfer induces a robust glycolytic switch in KCs, licensing their pro-inflammatory activation and amplifying hepatic injury. Using platelet-specific Aldoa knockout mice, we establish that platelet-derived ALDOA is essential for KCs metabolic reprogramming and disease progression in vivo. Pharmacological inhibition of ALDOA with Aldometanib markedly attenuated liver injury. Circulating ALDOA levels were elevated in patients with ALI and correlated with disease severity. These findings uncover a platelet–macrophage metabolic axis that drives ALI and nominate ALDOA as a therapeutic target and biomarker. Competing Interest Statement The authors have declared no competing interest.