{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:31:45Z","timestamp":1792009905932,"version":"4.4.0"},"reference-count":49,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"772","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,11,6]]},"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid\/bile acid\u2013mTOR\u2013FXR\/PPAR\u03b1 signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR\/CHKA\/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.<\/jats:p>","DOI":"10.1126\/scitranslmed.adh9940","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T13:58:18Z","timestamp":1730901498000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":52,"title":["Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1508-7084","authenticated-orcid":true,"given":"Jingjing","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Cholestatic Liver Diseases Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) Medical Research Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0131-9515","authenticated-orcid":true,"given":"Huaizheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Emergency, the Third Xiangya Hospital, Central South University, Changsha 410013, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3892-7464","authenticated-orcid":true,"given":"Xiaoxun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Cholestatic Liver Diseases Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) Medical Research Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4597-6547","authenticated-orcid":true,"given":"Nan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Cholestatic Liver Diseases Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) Medical Research Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4737-3712","authenticated-orcid":true,"given":"Ying","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Cholestatic Liver Diseases Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) Medical Research Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9434-897X","authenticated-orcid":true,"given":"Junping","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4275-9149","authenticated-orcid":true,"given":"Jinjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3193-1943","authenticated-orcid":true,"given":"Xiaoling","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9027-7307","authenticated-orcid":true,"given":"Ling","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Cholestatic Liver Diseases Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) Medical Research Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical 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Italy."},{"name":"Metabolic Diseases Research Unit, IRCCS Sacro Cuore\u2013Don Calabria Hospital, Negrar di Valpolicella 37024, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3423-0042","authenticated-orcid":true,"given":"Xinshou","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5643-4965","authenticated-orcid":true,"given":"Liqun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, the Second Affiliated Hospital, Army Medical University, Chongqing 400037, 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Third Military Medical University (Army Medical University), Chongqing 400038, China."},{"name":"Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) Medical Research Center, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.109"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.10.035"},{"key":"e_1_3_2_4_2","article-title":"First US drug approved for a liver disease surging around the world","author":"Ledford H.","unstructured":"H. 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