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During infections, innate immune cells detect pathogen\u2010associated molecular patterns (PAMPs) and produce proinflammatory cytokines. Among these, interleukin (IL)\u20106 is detected by hepatocytes, where it activates the production of the iron\u2010regulated hormone hepcidin that inhibits iron export from macrophages. Consequently, macrophages accumulate iron and hypoferremia (low plasma iron) develops. Whether Toll\u2010like receptors (TLRs) expressed on hepatocytes directly recognize PAMPs and contribute to hepcidin upregulation is still an open question. Stimulation of primary murine hepatocytes with a panel of PAMPs targeting TLRs 1\u20139 revealed that the TLR5 ligand flagellin and the TLR2:TLR6 ligand FSL1 upregulated hepcidin. Hepcidin was also induced upon treatment with heat\u2010killed <jats:italic>Staphylococcus aureus<\/jats:italic> (HKSA) and <jats:italic>Brucella abortus<\/jats:italic> (HKBA). The hepcidin response to flagellin, FSL1, HKSA, and HKBA started at an early time point, was independent of autocrine regulation by IL\u20106, and occurred through the TLR\u2010mitogen\u2010activated protein kinase (MAPK) axis. By analyzing a macrophage:hepatocyte co\u2010culture, we additionally show that the hepcidin response was dependent on TLR2:TLR6 expression in hepatocytes and independent of macrophage cytokine secretion. Ex vivo liver perfusion of mice with FSL1 and HKSA further revealed that PAMPs and pathogens can pass the sinusoidal barrier and reach hepatocytes to cause hepcidin upregulation in a TLR2:TLR6\u2010dependent manner. We conclude that hepatocytes can directly recognize PAMPs and pathogens and promote hepcidin upregulation in a macrophage and cytokine\u2010independent manner. This positions hepatocytes in the spotlight as potential direct drivers of iron restriction.<\/jats:p>","DOI":"10.1002\/hem3.70096","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T20:55:41Z","timestamp":1743800141000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Hepatocyte Toll\u2010like receptors contribute to the hepcidin inflammatory response to pathogens and pathogen\u2010derived ligands"],"prefix":"10.1002","volume":"9","author":[{"given":"Katharina","family":"Bonitz","sequence":"first","affiliation":[{"name":"Department of Pediatric Oncology, Hematology and Immunology Hopp Children's Cancer Center (KiTZ), University Hospital Heidelberg  Heidelberg 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