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Despite its prevalence, effective therapies are lacking. Recent genome\u2010wide association studies identified a common missense variant (rs2642438) in the Mitochondrial Amidoxime Reducing Component 1 (\n                      <jats:italic>MTARC1<\/jats:italic>\n                      ) gene that protects against liver cirrhosis without increasing cardiovascular disease risk. Biochemical and disease risk signatures associated with carriers of this missense variant also aligned with those of a known loss\u2010of\u2010function\n                      <jats:italic>MTARC1<\/jats:italic>\n                      variant, suggesting mARC1 inhibition as a potential MASLD treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To validate mARC1 loss\u2010of\u2010function as protective against MASLD, we generated\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      knockout (KO) mice and placed them on a choline\u2010deficient, L\u2010amino acid\u2010defined, high\u2010fat diet (CDAHFD). Effects of\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      KO on obesity and type 2 diabetes were explored using a high\u2010fat diet. Hepatocytes from\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      KO mice were isolated to explore the molecular mechanisms by which\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      KO impacts lipid metabolism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      KO mice exhibited no vital growth or development defects. With a high\u2010fat diet\u2010induced obesity model, obese\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      KO mice exhibited reduced liver mass and lower cholesterol levels, with no effect on glucose homeostasis. In a CDAHFD\u2010induced MASLD model, mARC1 deficiency significantly reduced liver steatosis, profibrosis, and inflammation. Untargeted metabolomics profiling further showed hepatic enrichment of phospholipids in\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      KO mice. Primary hepatocytes isolated from\n                      <jats:italic>Mtarc1<\/jats:italic>\n                      KO mice exhibited reduced lipid droplet accumulation, decreased fatty acid uptake, and increased lipid secretion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support mARC1 inhibition as a promising therapeutic strategy for MASLD\/MASH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70507","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:35:29Z","timestamp":1768293329000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Loss of\n                    <i>Mtarc1<\/i>\n                    Protects Against Steatotic Liver Disease in Mice"],"prefix":"10.1111","volume":"46","author":[{"given":"Xiaofei","family":"Yin","sequence":"first","affiliation":[{"name":"Cardiovascular Disease Initiative Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Bickerton","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-2066","authenticated-orcid":false,"given":"Bryan","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Arduini","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative Broad Institute of MIT and Harvard  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