Hepatocyte SAMHD1 Deficiency Attenuates Hepatic Steatosis via Suppression of SREBP Activation in a Mouse Model of Metabolic-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disorders and a growing public health concern. Sterile alpha motif and HD domain-containing protein 1 (SAMHD1), a dNTP triphosphohydrolase, is known for its roles in nucleotide metabolism, antiviral defense, and immune regulation, but its function in hepatocytes and contribution to MASLD pathogenesis remain unclear. In this study, we observed that hepatic SAMHD1 expression was markedly increased in MASLD patient samples and diet-induced MASLD mouse models. In vitro, mimicking MASLD-associated dyslipidemia with palmitic acid, oleic acid, and cholesterol upregulated SAMHD1 expression, an IFN-γ-induced protein, accompanied by increased IFN-γ receptor 1 expression and STAT1 activation in HepG2 cells. Functional studies using SAMHD1-overexpressing and knockdown hepatic cell lines, as well as hepatocyte-specific AAV-mediated SAMHD1 overexpression in vivo, demonstrated that SAMHD1 promoted lipid droplet accumulation. Conversely, hepatocyte-specific SAMHD1 knockout reduced steatosis and liver injury in diet-induced MASLD mouse models. Mechanistically, SAMHD1 enhanced the proteolytic activation of SREBP1 and SREBP2 by upregulating SCAP, S1P, and S2P in a cohesin complex-dependent manner. Collectively, these findings identify hepatocyte SAMHD1 as a promoter of liver steatosis through SREBP activation and highlight it as a potential therapeutic target for MASLD.