Supplementation of L-aspartate corrects MASLD and MASH in mice by inhibiting platelet-hepatocyte interaction-mediated mitochondrial fragmentation via the ATP-P2X7-NEK7-DRP1 axis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide prevalent metabolic disorder with increasing demands for therapeutic agents. L-aspartate is a nonessential amino acid that has great potential for curing liver disease. However, the therapeutic potential of L-aspartate against MASLD and its severe form metabolic dysfunction-associated steatohepatitis (MASH), as well as its metabolic regulation mode, are not well documented. Here we found that plasma and liver L-aspartate levels were decreased and negatively correlated with the severity of MASLD in mice and humans. L-aspartate supplementation in mice reversed the manifestations of both MASLD and MASH and these were correlated with improvements in hepatic mitochondrial quality and oxidation. The results of joint transcriptome and metabolomics analyses revealed that the metabolite cGMP and platelet activation were highly annotated after a single L-aspartate treatment. Notably, L-aspartate treatment increased cGMP levels in platelets and blocked platelet activation and aggregation, thereby suppressing activated platelet-derived ATP secretion and its mediated P2X7-NEK7-DRP1 axis hyperactivation in hepatocytes. Correspondingly, L-aspartate addition reversed the ATP-induced increases in oleatic acid-induced mitochondrial fragmentation and lipid accumulation. Interestingly, treatment with either the antiplatelet agent aspirin or the P2X7 inhibitor or NEK7 knockdown corrected oleatic acid + ATP-induced exacerbations of mitochondrial fragmentation and lipid accumulation in hepatocytes or ameliorated MASLD in mice. Notably, the L-aspartate increased cGMP levels in platelets was correlated with reductions in the plasma level of its inducers, including ADP and thrombin. These data together indicate that activated platelet-mediated mitochondrial fragmentation in hepatocytes is a pivotal driving force for MASLD and MASH. Blocking platelet activation underlies the therapeutic potential and metabolic regulation of L-aspartate against MASLD and MASH.