{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T08:34:12Z","timestamp":1793003652579,"version":"4.5.0"},"reference-count":45,"publisher":"Portland Press Ltd.","issue":"11","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82130084 82403952"],"award-info":[{"award-number":["82130084 82403952"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Postdoctoral Fellowship Program of CPSF","award":["GZB20250992"],"award-info":[{"award-number":["GZB20250992"]}]},{"name":"Applied Basic Research Program of The General Hospital of Western Theater Command","award":["2024-YGTC-B11"],"award-info":[{"award-number":["2024-YGTC-B11"]}],"id":[{"id":"https:\/\/ror.org\/009kr6r15","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,11,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Acute-on-chronic liver failure (ACLF) is an acute and severe syndrome with high mortality and limited therapeutic options. Excessive systemic inflammation, which drives hepatocyte dysfunction and programmed cell death, constitutes the hallmark feature of ACLF progression. PANoptosis, a coordinated form of apoptosis, necroptosis, and pyroptosis, has been implicated in ACLF pathogenesis, while its precise regulatory mechanisms remain elusive. Our previous studies have revealed the cross-talk between CD147 and systemic inflammation, while the specific function of CD147 in ACLF progression remains poorly characterized. The present study was aimed at elucidating the role of CD147 in regulating PANoptosis during ACLF progression. Bioinformatics analysis indicated that PANoptosis activation was strongly correlated with inflammatory receptor CD147. Both mRNA and protein expression of CD147 were markedly up-regulated in ACLF mice and patients. Moreover, CD147 blockade inhibited PANoptosis activation and alleviated liver injury in vivo, indicating a pivotal role of CD147 in driving ACLF progression. Using co-immunoprecipitation coupled with mass spectrometry, we identified S100A8\/A9 as the top up-regulated interacting partner of CD147, and elevated hepatic S100A8\/A9 expression was further validated. In AML12 cells, S100A8\/A9 combined with IFN-\u03b3 triggered hepatocyte PANoptosis in a CD147-dependent manner. Furthermore, S100A8\/A9 combined with IFN-\u03b3 promoted the phosphorylation of p38 MAPK, HUWE1 expression, and K27-linked ubiquitination of AIM2, whereas these effects were suppressed by CD147 inhibition. Additionally, pharmacological inhibition of p38 MAPK effectively suppressed HUWE1 expression and PANoptosis activation. Collectively, our findings highlight that the elevated S100A8\/A9 drives hepatocyte PANoptosis via CD147-p38 MAPK-HUWE1 axis and exhibit potential as a promising therapeutic strategy for ACLF.<\/jats:p>","DOI":"10.1042\/cs20260416","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:08:06Z","timestamp":1790773686000},"page":"2429-2445","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD147 drives acute-on-chronic liver failure progression by triggering hepatocyte PANoptosis"],"prefix":"10.1042","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4007-228X","authenticated-orcid":false,"given":"Hao","family":"Li","sequence":"first","affiliation":[{"name":"1Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China"},{"name":"2Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China"},{"name":"3Department of Laboratory and Pathology, Lintong Rehabilitation and Convalescent Center, Xi'an, Shaanxi, 710000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wu","sequence":"additional","affiliation":[{"name":"2Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanhong","family":"Tang","sequence":"additional","affiliation":[{"name":"2Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijie","family":"Bian","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-4623","authenticated-orcid":false,"given":"Zhi-Nan","family":"Chen","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,10,26]]},"reference":[{"key":"2026102604014440000_B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12072-024-10773-4","article-title":"Acute-on-chronic liver failure (ACLF): the \u2018Kyoto Consensus\u2019-steps from Asia","volume":"19","author":"Choudhury","year":"2025","journal-title":"Hepatol. Int."},{"key":"2026102604014440000_B2","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/s41575-025-01159-4","article-title":"Acute-on-chronic liver failure: pathophysiological mechanisms and clinical management","volume":"23","author":"Sarin","year":"2026","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2026102604014440000_B3","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.1111\/jgh.13799","article-title":"Systemic inflammatory response syndrome in acute-on-chronic liver failure: relevance of \u2018golden window\u2019: a prospective study","volume":"32","author":"Choudhury","year":"2017","journal-title":"J. Gastroenterol. Hepatol."},{"key":"2026102604014440000_B4","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/j.jhep.2020.11.048","article-title":"The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis","volume":"74","author":"Arroyo","year":"2021","journal-title":"J. Hepatol."},{"key":"2026102604014440000_B5","doi-asserted-by":"publisher","first-page":"935160","DOI":"10.3389\/fimmu.2022.935160","article-title":"The immune pathogenesis of acute-on-chronic liver failure and the danger hypothesis","volume":"13","author":"Qiang","year":"2022","journal-title":"Front Immunol."},{"key":"2026102604014440000_B6","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1002\/hep.28740","article-title":"Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure","volume":"64","author":"Cl\u00e0ria","year":"2016","journal-title":"Hepatology"},{"key":"2026102604014440000_B7","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1038\/s12276-023-01078-x","article-title":"Diversity and complexity of cell death: a historical review","volume":"55","author":"Park","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"2026102604014440000_B8","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.jhep.2020.01.011","article-title":"Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure","volume":"73","author":"Engelmann","year":"2020","journal-title":"J. Hepatol."},{"key":"2026102604014440000_B9","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41419-021-04442-9","article-title":"The role of RIPK1 mediated cell death in acute on chronic liver failure","volume":"13","author":"Kondo","year":"2021","journal-title":"Cell Death Dis."},{"key":"2026102604014440000_B10","doi-asserted-by":"publisher","first-page":"101446","DOI":"10.1016\/j.jcmgh.2024.101446","article-title":"A novel multi-organ male model of alcohol-induced acute-on-chronic liver failure reveals NET-mediated hepatocellular death, which is prevented by RIPK3 Inhibition","volume":"19","author":"Ortega-Ribera","year":"2024","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"2026102604014440000_B11","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1097\/HEP.0000000000000868","article-title":"NK-cell-elicited gasdermin-D-dependent hepatocyte pyroptosis induces neutrophil extracellular traps that facilitate HBV-related acute-on-chronic liver failure","volume":"81","author":"Zhao","year":"2025","journal-title":"Hepatology"},{"key":"2026102604014440000_B12","doi-asserted-by":"publisher","first-page":"406","DOI":"10.3389\/fcimb.2019.00406","article-title":"ZBP1 and TAK1: master regulators of NLRP3 inflammasome\/pyroptosis, apoptosis, and necroptosis (PAN-optosis)","volume":"9","author":"Malireddi","year":"2019","journal-title":"Front Cell Infect Microbiol."},{"key":"2026102604014440000_B13","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.2174\/0113816128404910250912133524","article-title":"PANoptosis in cytokine release syndrome: bridging the gap between inflammation and cell death","volume":"32","author":"Eltaib","year":"2025","journal-title":"Curr. Pharm. Des."},{"key":"2026102604014440000_B14","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/s10565-025-10112-9","article-title":"Emerging role of PANoptosis in pathogen infection and systemic diseases","volume":"41","author":"Cai","year":"2025","journal-title":"Cell Biol. Toxicol."},{"key":"2026102604014440000_B15","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/s41598-023-50720-1","article-title":"PANoptosis-like death in acute-on-chronic liver failure injury","volume":"14","author":"Ye","year":"2024","journal-title":"Sci. Rep."},{"key":"2026102604014440000_B16","doi-asserted-by":"publisher","first-page":"e18884","DOI":"10.1002\/advs.202518884","article-title":"CD147\/Basigin: from integrative molecular hub to translational therapeutic target","volume":"13","author":"Yang","year":"2025","journal-title":"Adv. Sci. (Weinh)"},{"key":"2026102604014440000_B17","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/s41423-019-0201-9","article-title":"ACPAs promote IL-1\u03b2 production in rheumatoid arthritis by activating the NLRP3 inflammasome","volume":"17","author":"Dong","year":"2020","journal-title":"Cell Mol. Immunol."},{"key":"2026102604014440000_B18","doi-asserted-by":"publisher","first-page":"784","DOI":"10.3389\/fcell.2020.00784","article-title":"Deficiency of CD147 attenuated non-alcoholic steatohepatitis progression in an NLRP3-dependent manner","volume":"8","author":"Zhang","year":"2020","journal-title":"Front Cell Dev. Biol."},{"key":"2026102604014440000_B19","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41392-021-00760-8","article-title":"CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma","volume":"6","author":"Geng","year":"2021","journal-title":"Signal Transduct. Target Ther."},{"key":"2026102604014440000_B20","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.cell.2020.11.025","article-title":"Synergism of TNF-\u03b1 and IFN-\u03b3 triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes","volume":"184","author":"Karki","year":"2021","journal-title":"Cell"},{"key":"2026102604014440000_B21","doi-asserted-by":"publisher","first-page":"16463","DOI":"10.1002\/jcp.28314","article-title":"MFGE8 protects against CCl4-induced liver injury by reducing apoptosis and promoting proliferation of hepatocytes","volume":"234","author":"Li","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"2026102604014440000_B22","doi-asserted-by":"publisher","first-page":"1197152","DOI":"10.3389\/fimmu.2023.1197152","article-title":"PANoptosis-based molecular subtyping and HPAN-index predicts therapeutic response and survival in hepatocellular carcinoma","volume":"14","author":"Song","year":"2023","journal-title":"Front Immunol."},{"key":"2026102604014440000_B23","doi-asserted-by":"publisher","first-page":"6301","DOI":"10.1172\/JCI138234","article-title":"HUWE1 mediates inflammasome activation and promotes host defense against bacterial infection","volume":"130","author":"Guo","year":"2020","journal-title":"J. Clin. Invest."},{"key":"2026102604014440000_B24","doi-asserted-by":"publisher","first-page":"101576","DOI":"10.1016\/j.xcrm.2024.101576","article-title":"Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts","volume":"5","author":"Chen","year":"2024","journal-title":"Cell Rep. Med."},{"key":"2026102604014440000_B25","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1158\/0008-5472.CAN-11-3843","article-title":"S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis","volume":"73","author":"Hibino","year":"2013","journal-title":"Cancer Res."},{"key":"2026102604014440000_B26","doi-asserted-by":"publisher","first-page":"115674","DOI":"10.1016\/j.biopha.2023.115674","article-title":"S100A8\/A9: an emerging player in sepsis and sepsis-induced organ injury","volume":"168","author":"Wang","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"2026102604014440000_B27","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/s41419-020-03378-w","article-title":"M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis","volume":"12","author":"Bai","year":"2021","journal-title":"Cell Death Dis."},{"key":"2026102604014440000_B28","doi-asserted-by":"publisher","first-page":"1347395","DOI":"10.3389\/fcell.2024.1347395","article-title":"G-CSF increases calprotectin expression, liver damage and neuroinflammation in a murine model of alcohol-induced ACLF","volume":"12","author":"Ortega-Ribera","year":"2024","journal-title":"Front Cell Dev. Biol."},{"key":"2026102604014440000_B29","doi-asserted-by":"publisher","first-page":"119887","DOI":"10.1016\/j.jep.2025.119887","article-title":"S100A9\/RAGE pathway regulation of mitophagy and the effect of JianPi LiShi YangGan formula in acute-on-chronic liver failure","volume":"348","author":"Li","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"2026102604014440000_B30","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/s41419-024-06849-6","article-title":"S100A8\/A9(hi) neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis","volume":"15","author":"Wang","year":"2024","journal-title":"Cell Death Dis."},{"key":"2026102604014440000_B31","doi-asserted-by":"publisher","first-page":"6164611","DOI":"10.1155\/2023\/6164611","article-title":"Plasma S100A8 and S100A9 are strong prognostic factors for hepatitis B virus-related acute-on-chronic liver failure","volume":"2023","author":"Zhang","year":"2023","journal-title":"Can J. Gastroenterol. Hepatol."},{"key":"2026102604014440000_B32","doi-asserted-by":"publisher","first-page":"4641","DOI":"10.1016\/j.csbj.2021.07.038","article-title":"From pyroptosis, apoptosis and necroptosis to PANoptosis: a mechanistic compendium of programmed cell death pathways","volume":"19","author":"Wang","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"2026102604014440000_B33","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1007\/s00018-022-04564-z","article-title":"Single cell analysis of PANoptosome cell death complexes through an expansion microscopy method","volume":"79","author":"Wang","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"2026102604014440000_B34","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1007\/s10495-024-02072-y","article-title":"Emerging role of PANoptosis in kidney diseases: molecular mechanisms and therapeutic opportunities","volume":"30","author":"Hou","year":"2025","journal-title":"Apoptosis"},{"key":"2026102604014440000_B35","doi-asserted-by":"publisher","first-page":"102489","DOI":"10.1016\/j.coi.2024.102489","article-title":"Inflammasomes and their role in PANoptosomes","volume":"91","author":"Nadella","year":"2024","journal-title":"Curr. Opin. Immunol."},{"key":"2026102604014440000_B36","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/s41586-021-03875-8","article-title":"AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence","volume":"597","author":"Lee","year":"2021","journal-title":"Nature"},{"key":"2026102604014440000_B37","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.4049\/jimmunol.2100449","article-title":"USP21 deubiquitinase regulates AIM2 inflammasome activation","volume":"207","author":"Hong","year":"2021","journal-title":"J. Immunol."},{"key":"2026102604014440000_B38","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1016\/j.celrep.2016.07.019","article-title":"TRIM11 suppresses AIM2 inflammasome by degrading AIM2 via p62-dependent selective autophagy","volume":"16","author":"Liu","year":"2016","journal-title":"Cell Rep."},{"key":"2026102604014440000_B39","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/s41419-022-04664-5","article-title":"STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS)","volume":"13","author":"Messaoud-Nacer","year":"2022","journal-title":"Cell Death Dis."},{"key":"2026102604014440000_B40","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1038\/s41419-022-05460-x","article-title":"FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM","volume":"13","author":"Bi","year":"2022","journal-title":"Cell Death Dis."},{"key":"2026102604014440000_B41","doi-asserted-by":"publisher","first-page":"e2412250","DOI":"10.1002\/advs.202412250","article-title":"HUWE1-mediated degradation of MUTYH facilitates DNA damage and mitochondrial dysfunction to promote acute kidney injury","volume":"12","author":"Yang","year":"2025","journal-title":"Adv. Sci. (Weinh)"},{"key":"2026102604014440000_B42","doi-asserted-by":"publisher","first-page":"4579","DOI":"10.1093\/nar\/gkv325","article-title":"DNA damage-induced activation of CUL4B targets HUWE1 for proteasomal degradation","volume":"43","author":"Yi","year":"2015","journal-title":"Nucleic. Acids. Res."},{"key":"2026102604014440000_B43","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1038\/s41388-023-02928-8","article-title":"The E3 ligase HUWE1 increases the sensitivity of CRC to oxaliplatin through TOMM20 degradation","volume":"43","author":"Lee","year":"2024","journal-title":"Oncogene"},{"key":"2026102604014440000_B44","doi-asserted-by":"publisher","first-page":"e2400611","DOI":"10.1002\/advs.202400611","article-title":"CD147-K148me2-driven tumor cell-macrophage crosstalk provokes NSCLC immunosuppression via the CCL5\/CCR5 axis","volume":"11","author":"Wang","year":"2024","journal-title":"Adv. Sci. (Weinh)"},{"key":"2026102604014440000_B45","doi-asserted-by":"publisher","first-page":"1702689","DOI":"10.3389\/fimmu.2026.1702689","article-title":"Cross-species hepatic transcriptomics identify conserved immune-metabolic reprogramming in acute-on-chronic liver failure progression","volume":"17","author":"Chen","year":"2026","journal-title":"Front Immunol."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/140\/11\/2429\/992554\/cs-2026-0416.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/140\/11\/2429\/992554\/cs-2026-0416.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T08:01:52Z","timestamp":1793001712000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/140\/11\/2429\/238131\/CD147-drives-acute-on-chronic-liver-failure"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,26]]},"references-count":45,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,11,11]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20260416","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,11]]},"published":{"date-parts":[[2026,10,26]]}}}