SUMOylation-driven nuclear translocation of HSF2BP alleviates MASLD via COX6A1-dependent mitochondrial reprogramming.

Metabolic dysfunction-associated steatotic liver disease (MASLD) remains a major global health burden with limited therapeutic options. Heat shock factor 2 binding protein (HSF2BP), originally characterized as a germ cell-specific regulator of meiosis, is significantly upregulated in both MASLD patient livers and high-fat diet (HFD)-fed mice. Here, we identify HSF2BP as a key metabolic regulator in hepatocytes that alleviates hepatic lipid accumulation by enhancing mitochondrial function. Hepatocyte-specific overexpression of HSF2BP improves glucose tolerance, reduces lipid deposition, and increases mitochondrial respiration, whereas its knockout exacerbates steatosis. Mechanistically, we show that HSF2BP undergoes SUMOylation through interaction with UBC9, promoting its nuclear translocation and triggering an upregulation of COX6A1, a core subunit of mitochondrial complex IV. This process is impaired in MASLD due to global suppression of hepatic SUMOylation. Pharmacological inhibition of SUMOylation using TAK-981 abolishes the protective effect of HSF2BP against hepatic steatosis, whereas enhancing SUMOylation through UBC9 overexpression or treatment with the SUMO activator N106 markedly ameliorates lipid accumulation in the liver. Collectively, our findings uncover a SUMOylation-dependent mechanism by which HSF2BP regulates mitochondrial integrity and lipid homeostasis, providing a promising therapeutic axis for MASLD.