Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of hepatic disorders that begins with simple steatosis and can advance to nonalcoholic steatohepatitis, potentially progressing further to fibrosis, cirrhosis, and hepatocellular carcinoma. At present, no pharmacological agent has received approval for the treatment of NAFLD-related hepatic steatosis. This situation highlights the urgent requirement for more effective interventions capable of modulating lipid metabolism and preventing the advancement from steatosis to more severe chronic liver conditions. Previous investigations have shown that apoptotic vesicles (apoVs) generated during programmed cell death hold considerable promise in maintaining liver homeostasis. Nevertheless, their capacity to alleviate NAFLD remains unexplored. In the current study, apoVs derived from platelets (PLT-apoVs) and from mesenchymal stem cells (MSC-apoVs) were administered in models of NAFLD. PLT-apoVs demonstrated more pronounced efficacy in reducing high-fat diet-induced hepatic lipid accumulation than MSC-apoVs. Proteomic profiling identified and confirmed apolipoprotein A-II (APOA2) as a critical mediator of apoV-regulated adipogenesis in MSCs, positioning it as a promising target for optimizing apoV-based therapies in lipid metabolism disorders. The elevated APOA2 content in PLT-apoVs accounted for their superior therapeutic performance relative to MSC-apoVs. These findings establish a foundation for the development of apoV-based strategies in the management of NAFLD.
