Development of SOCS1 mimetics as novel approach to harmonize inflammation, oxidative stress, and fibrogenesis in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease, encompassing a spectrum from simple steatosis to steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. As part of metabolic syndrome, MASLD/MASH is characterized by inflammation, oxidative stress, and fibrosis, highlighting the need for targeted therapies. The dysregulation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and its negative regulators the suppressors of cytokine signaling (SOCS), plays a critical role in liver function and contributes to MASLD progression. AIM: Based on a SOCS1 functional domain, we developed mimetic peptides (linear and cyclic) targeting JAK activity and assessed their hepatoprotective potential in experimental MASLD/MASH. RESULTS: In dietary mouse models of MASLD/MASH, the administration of peptides ameliorated liver damage at both early and advanced stages, as evidenced by significant decreases in serum transaminases and hepatic content of lipids, inflammatory cells, and collagen. Treatment attenuated hepatic STAT1/3 activation and downregulated genes involved in inflammation, fibrosis, and lipid metabolism. Livers from treated mice exhibited lower levels of oxidative damage markers, reduced expression of NADPH oxidase 1 (NOX1), and upregulation of the antioxidant genes catalase and superoxide dismutase. In vitro, the peptides were safe for hepatocytes at different doses and effectively counteracted palmitate-induced cytotoxicity, superoxide anion production, and cytokine and NOX1 expression, while increasing anti-inflammatory and antioxidant genes. CONCLUSIONS: SOCS1 mimetic peptides exhibit hepatoprotective effects in experimental MASLD/MASH by modulating lipotoxicity, inflammation, redox balance and fibrogenesis. This proof-of-concept supports their potential as candidates for preclinical MASLD therapy development.