{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:22:15Z","timestamp":1785410535707,"version":"3.56.0"},"reference-count":33,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["MOST 114-2314-B-006-095-MY3"],"award-info":[{"award-number":["MOST 114-2314-B-006-095-MY3"]}]},{"DOI":"10.13039\/501100004844","name":"National Cheng Kung University Hospital","doi-asserted-by":"crossref","award":["NCKUH-11408010"],"award-info":[{"award-number":["NCKUH-11408010"]}],"id":[{"id":"10.13039\/501100004844","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004844","name":"National Cheng Kung University Hospital","doi-asserted-by":"crossref","award":["NCKUH-11403037"],"award-info":[{"award-number":["NCKUH-11403037"]}],"id":[{"id":"10.13039\/501100004844","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004844","name":"National Cheng Kung University Hospital","doi-asserted-by":"crossref","award":["NCKUH-11403038"],"award-info":[{"award-number":["NCKUH-11403038"]}],"id":[{"id":"10.13039\/501100004844","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004844","name":"National Cheng Kung University Hospital","doi-asserted-by":"crossref","award":["NCKUH-11404023"],"award-info":[{"award-number":["NCKUH-11404023"]}],"id":[{"id":"10.13039\/501100004844","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004844","name":"National Cheng Kung University Hospital","doi-asserted-by":"crossref","award":["NCKUH-11404021"],"award-info":[{"award-number":["NCKUH-11404021"]}],"id":[{"id":"10.13039\/501100004844","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004844","name":"National Cheng Kung University Hospital","doi-asserted-by":"crossref","award":["NCKUH-11404071"],"award-info":[{"award-number":["NCKUH-11404071"]}],"id":[{"id":"10.13039\/501100004844","id-type":"DOI","asserted-by":"crossref"}]},{"award":["NCKUH-11408010"],"award-info":[{"award-number":["NCKUH-11408010"]}],"id":[{"id":"https:\/\/ror.org\/04zx3rq17","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NCKUH-11403037"],"award-info":[{"award-number":["NCKUH-11403037"]}],"id":[{"id":"https:\/\/ror.org\/04zx3rq17","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NCKUH-11403038"],"award-info":[{"award-number":["NCKUH-11403038"]}],"id":[{"id":"https:\/\/ror.org\/04zx3rq17","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NCKUH-11404023"],"award-info":[{"award-number":["NCKUH-11404023"]}],"id":[{"id":"https:\/\/ror.org\/04zx3rq17","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NCKUH-11404021"],"award-info":[{"award-number":["NCKUH-11404021"]}],"id":[{"id":"https:\/\/ror.org\/04zx3rq17","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NCKUH-11404071"],"award-info":[{"award-number":["NCKUH-11404071"]}],"id":[{"id":"https:\/\/ror.org\/04zx3rq17","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepassocin, also known as fibrinogen-like protein 1 (FGL-1), is a liver-derived secretory protein initially identified as a mitogenic factor involved in hepatocyte proliferation and liver regeneration. Increasing evidence has subsequently suggested that FGL-1 functions as a hepatokine linking hepatic metabolic stress to systemic metabolic regulation. Experimental and clinical studies have demonstrated that circulating FGL-1 levels are associated with obesity, insulin resistance, metabolic dysfunction-associated steatotic liver disease (MASLD), and type 2 diabetes mellitus (T2DM). Mechanistically, FGL-1 appears to contribute to metabolic dysfunction by impairing insulin signaling and promoting hepatic lipid accumulation, although its precise molecular targets remain incompletely defined. In addition to its metabolic roles, FGL-1 has been identified as a major ligand of lymphocyte activation gene-3 (LAG-3), implicating it in immune modulation and tumor progression, particularly in hepatocellular carcinoma (HCC). However, most available human data are observational, and conflicting findings from experimental models suggest that FGL-1 may function as a context-dependent mediator rather than a purely pathogenic factor. Given the expanding but sometimes conflicting evidence, a comprehensive understanding of FGL-1 biology may provide important insights into the complex interactions among hepatic stress responses, metabolic dysfunction, and immune regulation. This review therefore examines the current evidence regarding the physiological and pathological roles of FGL-1 and highlights key unresolved questions that may influence future translational research and therapeutic development.<\/jats:p>","DOI":"10.3390\/ijms27135699","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T05:48:16Z","timestamp":1782366496000},"page":"5699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepassocin (FGL-1) as a Hepatokine in Liver Physiology and Metabolic Dysfunction: A Narrative Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Hung-Chih","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiong-Ping","family":"Hii","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Chi-Mei Medical Center, Tainan 710, Taiwan"},{"name":"Department of Nursing, Min-Hwei Junior College of Health Care Management, Tainan 736, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Pi","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0611-8427","authenticated-orcid":false,"given":"Hung-Tsung","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan"},{"name":"Tong-Yuan Diabetes Center, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Yu","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan"},{"name":"Tong-Yuan Diabetes Center, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3350-6548","authenticated-orcid":false,"given":"Horng-Yih","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan"},{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan"},{"name":"Tong-Yuan Diabetes Center, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1007\/s00125-016-3991-7","article-title":"A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes","volume":"59","author":"Wu","year":"2016","journal-title":"Diabetologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.cell.2018.11.010","article-title":"Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3","volume":"176","author":"Wang","year":"2019","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.mce.2017.10.014","article-title":"Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle","volume":"470","author":"Jung","year":"2018","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"292","DOI":"10.7150\/ijbs.66834","article-title":"Implication of the hepatokine, fibrinogen-like protein 1 in liver diseases, metabolic disorders and cancer: The need to harness its full potential","volume":"18","author":"Liu","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s40364-024-00601-0","article-title":"FGL1 and FGL2: Emerging regulators of liver health and disease","volume":"12","author":"Chen","year":"2024","journal-title":"Biomark. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"106677","DOI":"10.5493\/wjem.v15.i3.106677","article-title":"Fibrinogen superfamily proteins: Key regulators in hepatic disorders","volume":"15","author":"Qu","year":"2025","journal-title":"World J. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Huo, J.-L., Wang, Y.-T., Fu, W.-J., Lu, N., and Liu, Z.-S. (2022). The promising immune checkpoint LAG-3 in cancer immunotherapy: From basic research to clinical application. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.956090"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e70962","DOI":"10.1096\/fj.202501997R","article-title":"Ablation of Hepatocyte Derived- FGL1 Does Not Aggravate Metabolic Dysfunction-Associated Steatotic Liver Disease","volume":"39","author":"Personnaz","year":"2025","journal-title":"FASEB J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5279","DOI":"10.1111\/febs.16430","article-title":"HPS protects the liver against steatosis, cell death, inflammation, and fibrosis in mice with steatohepatitis","volume":"289","author":"Yang","year":"2022","journal-title":"FEBS J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.bbrc.2015.05.121","article-title":"Hepassocin is required for hepatic outgrowth during zebrafish hepatogenesis","volume":"463","author":"Gao","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/biof.1574","article-title":"Discovery of a role of the novel hepatokine, hepassocin, in obesity","volume":"46","author":"Huang","year":"2019","journal-title":"BioFactors"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2958","DOI":"10.1096\/fj.201901925R","article-title":"Targeting fibrinogen-like protein 1 is a novel therapeutic strategy to combat obesity","volume":"34","author":"Wu","year":"2019","journal-title":"FASEB J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.trsl.2020.01.001","article-title":"Role of placental fibrinogen-like protein 1 in gestational diabetes","volume":"218","author":"Kang","year":"2020","journal-title":"Transl. Res."},{"key":"ref_14","first-page":"7607","article-title":"A randomized placebo-controlled, double-blind study to investigate the effect of a high oral loading dose of cholecalciferol in non-alcoholic fatty liver disease patients, new insights on serum STAT-3 and hepassocin","volume":"27","author":"Alarfaj","year":"2023","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yang, Y., Chen, H., Wan, Y., Dong, D., Wang, X., Yao, S., Wang, P., Xiang, S., Yang, X., and Yu, M. (2022). Protective Role of Hepassocin against Hepatic Endoplasmic Reticulum Stress in Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113325"},{"key":"ref_16","first-page":"1753","article-title":"Hepassocin activates Foxa2 in liver-derived cells to inhibit endoplasmic reticulum stress","volume":"39","author":"Wang","year":"2023","journal-title":"Chin. J. Biochem. Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Xi, F., and Liu, R. (2026). Unraveling fibrinogen-like protein 1\u2019s role in immune regulation. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1753785"},{"key":"ref_18","first-page":"5175","article-title":"Metabolic role of hepassocin in polycystic ovary syndrome","volume":"27","author":"Coskun","year":"2023","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"185","DOI":"10.2174\/1871530318666180716100543","article-title":"Overexpression of Hepassocin in Diabetic Patients with Nonalcoholic Fatty Liver Disease May Facilitate Increased Hepatic Lipid Accumulation","volume":"19","author":"Abdelmoemen","year":"2019","journal-title":"Endocr. Metab. Immune Disord.\u2014Drug Targets"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jena, J., Garc\u00eda-Pe\u00f1a, L.M., and Pereira, R.O. (2023). The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1264530"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S765","DOI":"10.1016\/S0302-2838(23)00582-1","article-title":"LAG-3\/FGL1 axis predicts response to immune checkpoint inhibitors in advanced urothelial carcinoma","volume":"83","author":"Yoshida","year":"2023","journal-title":"Eur. Urol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.immuni.2022.03.013","article-title":"Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity","volume":"55","author":"Maruhashi","year":"2022","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.tips.2025.05.008","article-title":"Exploring new frontiers in LAG-3 biology and therapeutics","volume":"46","author":"Wang","year":"2025","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yang, C., Qian, Q., Zhao, Y., Huang, B., Chen, R., Gong, Q., Ji, H., Wang, C., Xia, L., and You, Z. (2023). Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1112672"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1186\/s12967-020-02469-8","article-title":"Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis","volume":"18","author":"Guo","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yan, Q., Lin, H.-M., Zhu, K., Cao, Y., Xu, X.-L., Zhou, Z.-Y., Xu, L.-B., Liu, C., and Zhang, R. (2022). Immune Checkpoint FGL1 Expression of Circulating Tumor Cells Is Associated With Poor Survival in Curatively Resected Hepatocellular Carcinoma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.810269"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"123695","DOI":"10.1016\/j.biomaterials.2025.123695","article-title":"Nanoengineered T cell membrane-coated nanodecoys blocking LAG-3\/FGL1 to enhance cancer immunotherapy","volume":"326","author":"Xu","year":"2025","journal-title":"Biomaterials"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102424","DOI":"10.1016\/j.jceh.2024.102424","article-title":"The FGL-1\/LAG-3 Axis Is Associated With Disease Course in Alcohol-Associated Hepatitis: A Preliminary Report","volume":"15","author":"Pedersen","year":"2025","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"344","DOI":"10.4103\/jcrt.jcrt_2674_23","article-title":"Research advances in FGL1\/LAG3 for cancer diagnosis and treatment: From basics to clinical practice","volume":"21","author":"Hu","year":"2025","journal-title":"J. Cancer Res. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.tem.2021.05.002","article-title":"Sex hormone\u2013binding globulin: Biomarker and hepatokine?","volume":"32","author":"Simons","year":"2021","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s13045-021-01161-8","article-title":"Fibrinogen-like protein 1 (FGL1): The next immune checkpoint target","volume":"14","author":"Qian","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1016\/j.apsb.2023.12.011","article-title":"Development of LAG-3\/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy","volume":"14","author":"Qian","year":"2023","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.slasd.2023.04.003","article-title":"Development of a high-throughput TR-FRET screening assay for LAG-3\/FGL1 interaction","volume":"28","author":"Zhang","year":"2023","journal-title":"SLAS Discov. Adv. Sci. Drug Discov."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5699\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T04:57:30Z","timestamp":1782536250000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,24]]},"references-count":33,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135699"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135699","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,24]]}}}