NBDP ameliorates metabolic-associated steatohepatitis by suppressing IL-17/STAT3 signaling and caspase-mediated apoptosis.

Metabolic dysfunction-associated steatohepatitis (MASH) is driven by metabolic dysregulation, and progresses from simple steatosis to hepatocyte injury, inflammation, and fibrosis, making it a growing global health burden. MASH research has progressed rapidly in recent years, but effective therapeutic options remain limited. New agents with strong clinical efficacy are urgently needed. The NEMO-binding domain peptide (NBDP) is known to inhibit NF-κB activation and attenuate fibrosis in vivo. However, NBDP has not been studied in MASH. In this study, we employed a diet-induced MASH mouse model and an in vitro co-culture system to evaluate the therapeutic efficacy and underlying mechanisms of NBDP. Network pharmacology identified signal transducer and activator of transcription 3 (STAT3) as a key target of NBDP. Single-cell virtual knockout analysis further indicated that STAT3 overexpression closely mimics MASH progression. Histological and Western blot analyses showed that NBDP significantly restored hepatic architecture, as evidenced by marked reductions in lipid accumulation, inflammatory infiltration, extracellular matrix deposition, and hepatocyte apoptosis. Mechanistically, using STAT3-overexpressing MASH mice and a STAT3-knockdown/IL-17-stimulated in vitro co-culture system, we found that NBDP suppresses the IL-17/STAT3 signaling axis. This inhibition reduces fibrogenesis and caspase-dependent apoptosis during MASH progression. These findings suggest that NBDP ameliorates the main pathological features of MASH by targeting the IL-17/STAT3 pathway. Collectively, this study provides mechanistic insights and experimental validation for NBDP as a potential therapeutic strategy against MASH.