{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:09:08Z","timestamp":1791947348174,"version":"4.3.4"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Minor intron retention resulting from dysregulation of minor intron splicing factors is an emerging risk factor for the metabolic dysfunction\u2013associated 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\u2013independent mechanism. Notably, ZRSR1 cell-autonomously suppressed liver X receptor (LXR) activation\u2013induced de novo lipogenesis in both hepatocyte models and mouse models. Mechanistically, we demonstrate that ZRSR1 directly interacted with LXR\u03b1, and this physical interaction suppressed the binding activity of the LXR\u03b1\/retinoid X receptor \u03b1 (RXR\u03b1) 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\u2212SREBP1c 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.<\/jats:p>","DOI":"10.1093\/lifemeta\/loag020","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T11:22:35Z","timestamp":1783336955000},"source":"Crossref","is-referenced-by-count":1,"title":["ZRSR1 protects against obesity-associated hepatic lipogenesis independent of minor intron splicing"],"prefix":"10.1093","volume":"5","author":[{"given":"Yinkun","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai 200025,","place":["China"]},{"name":"Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People\u2019s Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine , Shanghai 200011,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyong","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai 200025,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinglin","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai 200025,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai 200025,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai 200025,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Sun","sequence":"additional","affiliation":[{"name":"Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine , Shanghai 200020,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"He","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People\u2019s Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine , Shanghai 200011,","place":["China"]},{"name":"Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities , Baise, Guangxi 533000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai 200025,","place":["China"]},{"name":"Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine , Shanghai 200020,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0949-3409","authenticated-orcid":false,"given":"Xu-Yun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai 200025,","place":["China"]},{"name":"Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine , Shanghai 200020,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"2026080508564378800_loag020-B1","doi-asserted-by":"crossref","first-page":"e0251","DOI":"10.1097\/HC9.0000000000000251","article-title":"The burden of nonalcoholic fatty liver disease (NAFLD) is rapidly growing in every region of the world from 1990 to 2019","volume":"7","author":"Paik","year":"2023","journal-title":"Hepatol Commun"},{"key":"2026080508564378800_loag020-B2","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"2026080508564378800_loag020-B3","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/s41575-023-00846-4","article-title":"Recompensation in cirrhosis: unravelling the evolving natural history of nonalcoholic fatty liver disease","volume":"21","author":"Feng","year":"2024","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2026080508564378800_loag020-B4","doi-asserted-by":"crossref","first-page":"329","DOI":"10.14218\/JCTH.2021.00178","article-title":"Metabolic-associated fatty liver disease (MAFLD): a multi-systemic disease beyond the liver","volume":"10","author":"Kaya","year":"2022","journal-title":"J Clin Transl Hepatol"},{"key":"2026080508564378800_loag020-B5","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41575-023-00754-7","article-title":"Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment","volume":"20","author":"Llovet","year":"2023","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2026080508564378800_loag020-B6","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1016\/j.jhep.2023.08.030","article-title":"Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): beyond insulin resistance","volume":"79","author":"Hutchison","year":"2023","journal-title":"J Hepatol"},{"key":"2026080508564378800_loag020-B7","doi-asserted-by":"crossref","first-page":"100018","DOI":"10.1016\/j.pharmr.2024.100018","article-title":"Pharmacological treatment for metabolic dysfunction-associated steatotic liver disease and related disorders: current and emerging therapeutic options","volume":"77","author":"Zhang","year":"2025","journal-title":"Pharmacol Rev"},{"key":"2026080508564378800_loag020-B8","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat Med"},{"key":"2026080508564378800_loag020-B9","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S1097-2765(00)80292-0","article-title":"Evolutionary fates and origins of U12-type introns","volume":"2","author":"Burge","year":"1998","journal-title":"Mol Cell"},{"key":"2026080508564378800_loag020-B10","doi-asserted-by":"crossref","first-page":"4006","DOI":"10.1093\/nar\/29.19.4006","article-title":"A computational scan for U12-dependent introns in the human genome sequence","volume":"29","author":"Levine","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"2026080508564378800_loag020-B11","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1093\/nar\/gkl556","article-title":"Comprehensive splice-site analysis using comparative genomics","volume":"34","author":"Sheth","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"2026080508564378800_loag020-B12","first-page":"7066","article-title":"Comprehensive database and evolutionary dynamics of U12-type introns","volume":"48","author":"Moyer","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2026080508564378800_loag020-B13","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1038\/nrm1259","article-title":"Splicing double: insights from the second spliceosome","volume":"4","author":"Patel","year":"2003","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026080508564378800_loag020-B14","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.molcel.2024.12.017","article-title":"Structural basis of 5\u2019 splice site recognition by the minor spliceosome","volume":"85","author":"Zhao","year":"2025","journal-title":"Mol Cell"},{"key":"2026080508564378800_loag020-B15","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1101\/gad.1974810","article-title":"The U2AF35-related protein Urp contacts the 3\u2019 splice site to promote U12-type intron splicing and the second step of U2-type intron splicing","volume":"24","author":"Shen","year":"2010","journal-title":"Genes Dev"},{"key":"2026080508564378800_loag020-B16","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1128\/MCB.17.2.789","article-title":"Mouse U2af1-rs1 is a neomorphic imprinted gene","volume":"17","author":"Nabetani","year":"1997","journal-title":"Mol Cell Biol"},{"key":"2026080508564378800_loag020-B17","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1136\/jclinpath-2017-204440","article-title":"Identifying large indels in targeted next generation sequencing assays for myeloid neoplasms: a cautionary tale of the ZRSR1 pseudogene","volume":"70","author":"Ng","year":"2017","journal-title":"J Clin Pathol"},{"key":"2026080508564378800_loag020-B18","doi-asserted-by":"crossref","first-page":"4115","DOI":"10.3390\/ijms21114115","article-title":"Minor splicing factors Zrsr1 and Zrsr2 are essential for early embryo development and 2-cell-like conversion","volume":"21","author":"G\u00f3mez-Redondo","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2026080508564378800_loag020-B19","doi-asserted-by":"crossref","first-page":"10668","DOI":"10.3390\/ijms231810668","article-title":"Zrsr2 is essential for the embryonic development and splicing of minor introns in RNA and protein processing genes in zebrafish","volume":"23","author":"Weinstein","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2026080508564378800_loag020-B20","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.celrep.2018.03.028","article-title":"Impaired spermatogenesis, muscle, and erythrocyte function in U12 intron splicing-defective Zrsr1 mutant mice","volume":"23","author":"Horiuchi","year":"2018","journal-title":"Cell Rep"},{"key":"2026080508564378800_loag020-B21","doi-asserted-by":"crossref","first-page":"2934","DOI":"10.1111\/cas.15476","article-title":"Dysregulated minor intron splicing in cancer","volume":"113","author":"Nishimura","year":"2022","journal-title":"Cancer Sci"},{"key":"2026080508564378800_loag020-B22","doi-asserted-by":"crossref","first-page":"186478","DOI":"10.1172\/JCI186478","article-title":"Disrupted minor intron splicing activates reductive carboxylation-mediated lipogenesis to drive metabolic dysfunction-associated steatotic liver disease progression","volume":"135","author":"Fu","year":"2025","journal-title":"J Clin Invest"},{"key":"2026080508564378800_loag020-B23","first-page":"507","article-title":"SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease","volume":"21","author":"Kohjima","year":"2008","journal-title":"Int J Mol Med"},{"key":"2026080508564378800_loag020-B24","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nrm3312","article-title":"Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR","volume":"13","author":"Calkin","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026080508564378800_loag020-B25","doi-asserted-by":"crossref","first-page":"639757","DOI":"10.3389\/fendo.2021.639757","article-title":"Disrupted lipid metabolism in multiple sclerosis: a role for liver X receptors?","volume":"12","author":"Pineda-Torra","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026080508564378800_loag020-B26","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.1101\/gad.844900","article-title":"Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXR\u03b1 and LXR\u03b2","volume":"14","author":"Repa","year":"2000","journal-title":"Genes Dev"},{"key":"2026080508564378800_loag020-B27","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1042\/BJ20040162","article-title":"Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements","volume":"385","author":"Cagen","year":"2005","journal-title":"Biochem J"},{"key":"2026080508564378800_loag020-B28","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1002\/hep.23719","article-title":"Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites","volume":"52","author":"Neuschwander-Tetri","year":"2010","journal-title":"Hepatology"},{"key":"2026080508564378800_loag020-B29","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1210\/me.2013-1153","article-title":"Autophagy deficiency by hepatic FIP200 deletion uncouples steatosis from liver injury in NAFLD","volume":"27","author":"Ma","year":"2013","journal-title":"Mol Endocrinol"},{"key":"2026080508564378800_loag020-B30","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.cell.2004.09.013","article-title":"Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1\u03b1 null mice","volume":"119","author":"Lin","year":"2004","journal-title":"Cell"},{"key":"2026080508564378800_loag020-B31","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2014a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"2026080508564378800_loag020-B32","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"}],"container-title":["Life Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/lifemeta\/advance-article-pdf\/doi\/10.1093\/lifemeta\/loag020\/68732375\/loag020.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/lifemeta\/article-pdf\/5\/5\/loag020\/68732375\/loag020.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/lifemeta\/article-pdf\/5\/5\/loag020\/68732375\/loag020.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T12:56:58Z","timestamp":1785934618000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/lifemeta\/article\/doi\/10.1093\/lifemeta\/loag020\/8728808"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":32,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,7,24]]}},"URL":"https:\/\/doi.org\/10.1093\/lifemeta\/loag020","relation":{},"ISSN":["2755-0230"],"issn-type":[{"value":"2755-0230","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,10]]},"published":{"date-parts":[[2026,7,8]]},"article-number":"loag020"}}