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We found aberrant hepatic FGF21 and KC pool in human MASH-HCC. Lack of FGF21 up-regulated ALOX15, which converted the oxidized fatty acids to induce excessive KC death and mobilization of monocyte-derived macrophages (MoMFs) for KC replacement. Lack of FGF21 oversupplied free fatty acids for sphingosine-1-phosphate (S1P) cascade synthesis to mediate MASH-HCC transition via S1P-YAP signaling and cross-talk between tumor cells and macrophages. In conclusion, lack of FGF21 accelerated MASH-HCC transition via the S1P-AP signaling. Compromised MoMFs could present as tumor-associated macrophage phenotype rendering tumor immune microenvironment for MASH-HCC transition.<\/jats:p>","DOI":"10.1126\/sciadv.ado9311","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T17:58:43Z","timestamp":1729706323000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":18,"title":["Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9640-2025","authenticated-orcid":true,"given":"Xiaoju","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA."},{"name":"Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5906-148X","authenticated-orcid":true,"given":"Qianqian","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA."},{"name":"Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang 110122, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2253-1737","authenticated-orcid":true,"given":"Xingtong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA."},{"name":"Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1982-7131","authenticated-orcid":true,"given":"Wei","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA."},{"name":"Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110022, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7750-4579","authenticated-orcid":true,"given":"Yonglin","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1300-6431","authenticated-orcid":true,"given":"Emily","family":"Shore","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert C.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4656-4955","authenticated-orcid":true,"given":"Guoyue","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5584-1964","authenticated-orcid":true,"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-090514-013832"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29466"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/MCG.0000000000001229"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0025-6196(24)00530-5","article-title":"Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease","volume":"55","author":"Ludwig J.","year":"1980","unstructured":"J. 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