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Human genetic studies have identified mitochondrial amidoxime\u2010reducing component (MTARC1) variants associated with a reduced risk of MASLD, but the underlying mechanisms remain unclear. Here, we investigated the role of MTARC1 in fatty liver disease using in\u00a0vitro and in\u00a0vivo models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We generated global and liver\u2010specific\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      knockout mice, as well as models with genetic inhibition of\n                      <jats:italic>Pnpla2<\/jats:italic>\n                      ,\n                      <jats:italic>Lipa<\/jats:italic>\n                      ,\n                      <jats:italic>Pemt<\/jats:italic>\n                      and\n                      <jats:italic>Cept1<\/jats:italic>\n                      . We performed comprehensive biochemical, histological and integrated multi\u2010omics analyses. In\u00a0vitro cell culture models were used to delineate the mechanism by which MTARC1 regulates lipid metabolism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Global and liver specific knockout of\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      significantly protected against diet\u2010induced hepatic triglyceride accumulation, liver injury, inflammation, and fibrosis. These effects required triglyceride degradation via lipophagy and lipolysis. Multi\u2010omics profiling revealed that MTARC1 deficiency post\u2010transcriptionally upregulates glycerophospholipid (GPL) biosynthetic enzymes CEPT1 and PEMT, leading to altered phospholipid composition in lipid droplets. This remodelling reduced the size of lipid droplets (LD), increased their surface\u2010to\u2010volume ratio, and thereby enhanced their degradation. Knockdown of CEPT1 and PEMT reversed the hepatoprotective effects of MTARC1 deficiency.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings identify an MTARC1\u2010GPL biosynthesis\u2010LD degradation axis as a key regulator of hepatic triglyceride homeostasis and highlight MTARC1 inhibition as a promising therapeutic strategy for MASLD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70539","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T13:28:27Z","timestamp":1770298107000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>MTARC1<\/scp>\n                    Inactivation Remodels Lipid Droplets to Protect Against Metabolic Fatty Liver Disease"],"prefix":"10.1111","volume":"46","author":[{"given":"Meng","family":"Tie","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Basic Medical Science Anhui Medical University  Hefei China"},{"name":"Department of Biochemistry and Molecular Biology, College of Life Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Basic Medical Science Anhui Medical University  Hefei China"},{"name":"Department of Biochemistry and Molecular Biology, College of Life Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Life Sciences Anhui Medical University  Hefei 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