miR-150-5p promotes MASH progression through regulation of CTH-associated sulfur and redox metabolism.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive metabolic liver disease with few effective mechanism-based treatments. MicroRNAs (miRNAs) can coordinate disease-associated gene networks and have emerged as potential regulators and therapeutic targets in metabolic disease. Using an integrative cross-species framework that included a cynomolgus macaque model, human liver samples, and murine models of MASH, we identified dysregulated hepatocyte miR-150-5p as a conserved feature associated with disease progression. In human hepatocytes, miR-150-5p directly targeted cystathionine γ-lyase (CTH/CSE), a major hepatic hydrogen sulfide (H2S)-producing enzyme. miR-150-5p-mediated suppression of CTH contributed to reduce H2S-related signals, a lower GSH/GSSG ratio, increased oxidative stress-associated readouts, and lipid accumulation in hepatocytes. CTH re-expression attenuated these metabolic and redox-associated alterations, whereas pharmacological CTH/CSE inhibition produced corresponding changes, supporting a functional contribution of CTH to the effects of miR-150-5p. In parallel, elevated hepatocyte miR-150-5p increased TGF-β1 secretion and enhanced paracrine signals associated with hepatic stellate cell activation under lipotoxic conditions. Hepatocyte-specific inhibition of miR-150-5p using an AAV8-delivered sponge in mice with established MASH ameliorated steatosis, inflammation, and fibrotic remodeling and was associated with increased hepatic Cth expression and improvements in H2S-associated and redox-related parameters. These findings identify miR-150-5p-mediated regulation of CTH as a mechanism contributing to metabolic and redox-associated alterations in MASH and support further evaluation of hepatocyte miR-150-5p as a potential therapeutic target.