Zrsr1 Protects Against Obesity-Associated Hepatic Lipogenesis Independent of Minor Intron Splicing by Inhibiting the LXR-SREBP1c Axis [zrsr1 HFD]

Minor intron retention resulting from dysregulation of minor intron splicing factors is an emerging risk factor for the metabolic-associated steatotic liver disease (MASLD). However, whether impaired expression of these splicing factors exerts critical roles in MASLD progression independent of their minor intron splicing activity remains largely undefined. Here, we show that hepatic expression of the minor intron splicing factor Zrsr1 is significantly downregulated in mice fed a high-fat diet (HFD), while canonical minor intron splicing remains unperturbed. Hepatic Zrsr1 overexpression effectively mitigates HFD-induced obesity and insulin resistance, demonstrating that Zrsr1 expression protects MASLD progression via a minor intron splicing-independent mechanism. Notably, Zrsr1 cell-autonomously suppresses liver X receptor (LXR) activation-induced de novo lipogenesis in both hepatocyte models and mouse models. Mechanistically, we demonstrate that Zrsr1 directly interacts with LXRα, and this physical interaction suppresses the transactivation of the LXRα/retinoid X receptor α (RXRα) complex, thereby inhibiting the subsequent transcription of sterol regulatory element-binding protein 1c (Srebp1c). Collectively, these findings define a novel, splicing-independent function of the minor intron splicing factor Zrsr1 in mediating hepatic de novo lipogenesis via constraining the LXR-SREBP1c axis, which in turn mitigates MASLD progression. This work expands the functional repertoire of minor intron splicing factors beyond their classical splicing role, providing new insights into the molecular mechanisms underlying hepatic fatty acid metabolism and MASLD pathogenesis.