SOCS1-based therapeutic peptides improve liver disease and metabolic dysfunction in obesity and diabetes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a growing global health challenge, closely linked to obesity and type 2 diabetes mellitus. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a key mediator of inflammation and metabolic dysregulation in liver disease. This study investigates the therapeutic potential of a SOCS1-derived peptidomimetic (MiS1) in a mouse model of MASLD using obese, type 2 diabetic BTBR ob/ob mice. A six-week treatment with MiS1 (10 μg/g/day) significantly reduced body weight, serum transaminase levels, hepatic steatosis, and hepatocellular ballooning compared to untreated controls. MiS1-treated mice exhibited decreased hepatic triglyceride content, notably in palmitic (C16:0) and palmitoleic (C16:1n-7) acids, along with downregulation of key lipogenic enzymes. Inflammatory signaling was also attenuated, with lower expression of pro-inflammatory cytokines and increased expression of CD163, a marker of M2 anti-inflammatory macrophages. In vitro, MiS1 directly inhibited insulin-induced STAT3 phosphorylation and suppressed lipogenic gene expression in murine hepatocytes. These results demonstrate that JAK/STAT pathway inhibition via MiS1 ameliorates key pathological features of MASLD by concurrently targeting hepatic lipid metabolism and inflammation, highlighting its potential as a novel therapeutic approach for patients with obesity and diabetes.