SUMOylation of HMGCS1 triggers its ubiquitin-dependent degradation to alleviate hepatic steatosis

Background & aims: Despite recent approvals for noncirrhotic MASH with moderate-to-advanced fibrosis, incomplete response rates and the need for mechanistically distinct, durable, and broadly applicable therapies underscore an urgent need for additional drug development across the MASLD spectrum. Although SUMOylation regulates hepatic metabolism, its functional role and therapeutic potential in MASLD remain unclear. We aimed to determine whether modulating global hepatic SUMOylation influences MASLD progression and to identify the underlying molecular mechanisms.

Methods: Hepatic SUMOylation was assessed in human MASLD samples spanning simple steatosis to MASH with fibrosis (F1-F3) and in mice fed either a high-fat diet (HFD) or a methionine-choline-deficient (MCD) diet. SUMOylation was enhanced by overexpressing the E2 enzyme UBC9 or administering the activator N106, and inhibited using TAK-981. Proteomic profiling, co-immunoprecipitation, site-directed mutagenesis, and ubiquitination assays were employed to identify and validate downstream effectors. Genetic gain- and loss-of-function studies in vitro and in vivo were used to establish causal relationships.

Results: Hepatic SUMOylation was significantly downregulated in human MASLD and in murine models. Enhancing SUMOylation alleviated hepatic steatosis, whereas inhibiting it exacerbated lipid accumulation. Multi-omics analyses identified 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) as a central effector that is inversely regulated by SUMOylation. SUMOylation promotes HMGCS1 ubiquitination and proteasomal degradation, thereby suppressing Cholesterol biosynthesis. We further mapped the SUMO2/3 modification to lysine 305 of HMGCS1, catalyzed by the E3 Ligase RANBP2. Critically, the small-molecule activator N106 enhanced this pathway and robustly attenuated steatosis in vivo, an effect abolished by a SUMOylation-deficient HMGCS1 mutant.

Conclusions: Our study establishes global hepatic SUMOylation as a druggable regulatory node in MASLD and delineates a SUMO-ubiquitin pathway centered on HMGCS1. Pharmacological activation of this axis via N106 represents a promising preclinical therapeutic strategy, highlighting the potential of targeting the SUMOylation machinery in metabolic liver disease.