Selenoprotein H Functions as a PPARα Coactivator to Link Selenium Homeostasis to Hepatic Lipid Metabolism and Protect against Steatohepatitis

Selenium is an essential trace element whose dysregulation is associated with diverse disease risks; however, its specific role in hepatic metabolism remains poorly defined. Here we delineate a novel selenium‐selenoprotein H (SELENOH)‐PPARα signaling axis that is critical for hepatic lipid homeostasis. We first uncovered a global impairment of selenoprotein translation as a key feature of metabolic dysfunction‐associated steatohepatitis (MASH) in human patients and mouse models. Both dietary selenium supplementation and genetically rescuing selenoprotein biosynthesis attenuated MASH pathology, establishing a causal link. Through a targeted screen, we pinpointed SELENOH as the key hepatoprotective selenoprotein governing hepatic fatty acid oxidation (FAO). Diverging from the canonical redox functions of selenoproteins, SELENOH operates as a scaffolding coactivator for the nuclear receptor PPARα. SELENOH binds to ligand‐activated PPARα and orchestrates the assembly and chromatin recruitment of the PPARα‐P300 transactivation complex to drive FAO gene expression. This nexus is disrupted in MASH livers due to SELENOH deficiency but is reconstituted by selenium supplementation. These findings altogether define selenium homeostasis as a fundamental regulator of nuclear receptor function and unveil promising therapeutic avenues for MASH.