ZRSR1 protects against obesity-associated hepatic lipogenesis independent of minor intron splicing.

Minor intron retention resulting from dysregulation of minor intron splicing factors is an emerging risk factor for the metabolic dysfunction-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 (zinc finger CCCH-type, RNA-binding motif, and serine/arginine rich 1) was significantly downregulated in mice fed a high-fat diet (HFD), while canonical minor intron splicing remained unperturbed. Gain- and loss-of-function analyses in liver tissue confirmed that hepatic ZRSR1 negatively modulated HFD-triggered obesity and insulin resistance, indicating that ZRSR1 restrained MASLD progression through a minor intron splicing-independent mechanism. Notably, ZRSR1 cell-autonomously suppressed liver X receptor (LXR) activation-induced de novo lipogenesis in both hepatocyte models and mouse models. Mechanistically, we demonstrate that ZRSR1 directly interacted with LXRα, and this physical interaction suppressed the binding activity of the LXRα/retinoid X receptor α (RXRα) complex toward the promoter regions of its target genes including the sterol regulatory element-binding protein 1c (Srebp1c), consequently repressing the transcription of Srebp1c and its downstream lipogenic genes. 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 roles, providing new insights into the molecular mechanisms underlying hepatic fatty acid metabolism and MASLD pathogenesis.