Exercise and dietary interventions ameliorate MASLD via the hepatic PPARγ-miR-802-Psmd2 axis.

Background: MicroRNAs critically regulate metabolic dysfunction-associated steatotic liver disease (MASLD) progression and intervention. Lifestyle modifications, particularly exercise and time-restricted feeding (TRF), emerge as effective non-pharmacological strategies. Methods: MiR-802 expression was quantified in plasma exosomes and hepatic tissues of MASLD mouse models using quantitative PCR and sequencing. In vivo and in vitro gain-of-function and loss-of-function experiments assessed its regulatory effects on hepatic lipotoxicity, complemented by bioinformatic predictions and luciferase-based validation of upstream transcription factors and downstream targets. Functional crosstalk between miR-802 and its regulatory network was examined under lipotoxic conditions. Therapeutic interventions, including exercise and TRF, were implemented in high-fat diet fed mice, with subsequent evaluation of miR-802 expression dynamics. Results: Here, we show elevated miR-802 levels in plasma exosomes and livers of MASLD mice, with its inhibition reducing hepatocyte lipotoxicity. Mechanistically, peroxisome proliferator-activated receptor gamma (PPARγ) promotes miR-802 transcription, whereas miR-802 suppresses the proteasome 26S subunit ubiquitin receptor, non-ATPase 2 (Psmd2). Genetic and pharmacological modulation of PPARγ downregulates miR-802 and ameliorates MASLD. Notably, both exercise and TRF reduce hepatic PPARγ and miR-802 expression and improve MASLD via the PPARγ-miR-802-Psmd2 axis, revealing lifestyle modification-mediated epigenetic regulation in MASLD pathophysiology. Conclusion: This study reveals the PPARγ-miR-802-Psmd2 axis as a central regulatory mechanism in MASLD pathogenesis and innovatively links lifestyle interventions (exercise and TRF) to therapeutic effects via this pathway.