{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:44:42Z","timestamp":1789469082519,"version":"build-2803163510"},"reference-count":28,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003130","name":"FWO","doi-asserted-by":"publisher","award":["1220924N"],"award-info":[{"award-number":["1220924N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"FWO","doi-asserted-by":"publisher","award":["11P1I24N"],"award-info":[{"award-number":["11P1I24N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Research Foundation Flanders"},{"name":"Research Council of Ghent University","award":["SEPSIS\u2014S003122N"],"award-info":[{"award-number":["SEPSIS\u2014S003122N"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Sepsis induces profound alterations in liver function that contribute to disease progression. We previously demonstrated that peritoneal sepsis is associated with marked disruption of hepatic transcriptional programs, including loss-of-function of Hepatocyte Nuclear Factor 4 alpha (HNF4\u03b1), a master regulator of hepatic identity and metabolism. Using hepatocyte-specific HNF4\u03b1 knockout mice, we further showed that loss of HNF4\u03b1 is detrimental during peritoneal sepsis. Here, we investigated whether this response is conserved in pneumonia-induced sepsis and assessed its functional significance. Bulk liver RNA sequencing revealed that suppression of hepatic metabolic pathways and HNF4\u03b1 target genes are conserved features of both peritoneal and Streptococcus pneumoniae-induced sepsis. Unexpectedly, hepatocyte-specific HNF4\u03b1 deficiency was associated with lower bacterial burden and increased survival during pneumococcal sepsis. Mechanistically, this protective effect was dependent on neutrophils and not macrophages. These findings demonstrate that sepsis-induced hepatic HNF4\u03b1 dysregulation is conserved across distinct infectious etiologies but exerts context-dependent effects on disease outcome.<\/jats:p>","DOI":"10.3390\/ijms27188198","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:31:57Z","timestamp":1789464717000},"page":"8198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte HNF4\u03b1 Deficiency Protects Against Pneumococcal Sepsis Through a Neutrophil-Dependent Mechanism"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1844-6476","authenticated-orcid":false,"given":"Jolien","family":"Vandewalle","sequence":"first","affiliation":[{"name":"Center for Inflammation Research, VIB, 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Marah","family":"Heyerick","sequence":"additional","affiliation":[{"name":"Center for Inflammation Research, VIB, 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Steven","family":"Timmermans","sequence":"additional","affiliation":[{"name":"Center for Inflammation Research, VIB, 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-036X","authenticated-orcid":false,"given":"Claude","family":"Libert","sequence":"additional","affiliation":[{"name":"Center for Inflammation Research, VIB, 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","unstructured":"GBD 2021 Global Sepsis Collaborators (2025). 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