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Fructose\u20101,6\u2010bisphosphatase 1 (FBP1), a key gluconeogenic enzyme, has poorly defined roles in MASLD progression. Here, we show that FBP1 is consistently downregulated during MASLD progression, with a progressive decline from MASL to MASH in clinical specimens and key preclinical models. Mechanistically, FBP1 directly interacts with glycolytic enzymes Pyruvate kinase M2 (PKM2), Enolase 1 (ENO1), and Lactate Dehydrogenase A (LDHA) to form compartmentalized complexes, suppressing PKM2 activity and restricting excessive glycolysis and lipid accumulation in hepatocytes. Domain mapping defined the precise interaction interface between FBP1 189\u2013235 aa and PKM2 390\u2013531 aa, and disruption of this binding abrogated FBP1's glycolysis\u2010repressive effects in hepatocytes. In vivo, only liver\u2010specific overexpression of enzymatically inactive but binding\u2010competent FBP1 G260R, not its interaction\u2010deficient mutant FBP1 G260R\u2010\u0394189\u2010235, alleviated hepatic steatosis, inflammation, and fibrosis in diet\u2010induced MASLD mice. This study reveals a non\u2010canonical function of FBP1 independent of its enzymatic activity in regulating glycolytic complex assembly and identifies the FBP1\u2010PKM2 interaction as a novel candidate intervention target for MASLD.<\/jats:p>","DOI":"10.1002\/advs.77875","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FBP1\u2010Mediated Compartmentalization of Glycolytic Enzyme Complexes Suppresses PKM2 Function to Ameliorate MASLD Progression"],"prefix":"10.1002","author":[{"given":"Busong","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology Institute of Chinese Medicine Department of Laboratory Medicine Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Medical School of Nanjing University  Nanjing People's Republic of China"},{"name":"State Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences Nanjing University  Nanjing People's Republic of China"},{"name":"Chemistry and Biomedicine Innovation Center Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7899-9711","authenticated-orcid":false,"given":"Yiping","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology Institute of Chinese Medicine Department of Laboratory Medicine Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Medical School of Nanjing University  Nanjing People's Republic of China"},{"name":"Chemistry and Biomedicine Innovation Center Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University  Nanjing People's Republic of 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