Liu-Jun-Zi Decoction Alleviates Metabolic Dysfunction-Associated Steatohepatitis by Modulating Myogenic Irisin Mediated Skeletal Muscle-Liver Crosstalk

Background Metabolic dysfunction-associated fatty liver disease (MAFLD) is a major global chronic liver disorder, with metabolic dysfunction-associated steatohepatitis (MASH) representing its severe subtype. Liu-Jun-Zi Decoction (LJZD), a classical traditional Chinese medicine (TCM) formula, has shown clinical efficacy against MASH, however, its underlying mechanisms remain unclear. Purpose To investigate the molecular mechanism through which LJZD alleviates hepatic steatosis in MASH mice by restoring irisin secretion in skeletal muscle. Methods A MASH mouse model was established using a methionine and choline deficient (MCD) diet, followed by LJZD treatment. First, major chemical components of LJZD were identified via UHPLC-QE-MS. Subsequently, histopathological and biochemical analyses were performed to evaluate the effects of LJZD on MASH and skeletal muscle atrophy. Finally, the secretion of irisin in skeletal muscle was assessed, and bioinformatics analysis was used to screen downstream targets of irisin. Results LJZD significantly alleviated hepatic steatosis, injury, inflammation, and fibrosis in MASH mice while improving concomitant skeletal muscle atrophy. Furthermore, LJZD enhanced irisin secretion from skeletal muscle. Integrated transcriptomic analysis identified carboxylesterase 2A (CES2A) as a key hepatic downstream effector of irisin. Conclusion LJZD ameliorates MASH by promoting skeletal muscle irisin secretion, which upregulates hepatic CES2A to enhance lipid catabolism. In summary, current data extend the research scope on LJZD's pharmacological effects and suggest new approaches for clinical MASH treatment. LJZD alleviates hepatic steatosis by targeting skeletal muscle, indicating its potential as a therapeutic candidate for MASH.