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Here, we identify CRX-527, a TLR4 agonist, as a novel inducer of hepatocyte proliferation in both healthy mice and a model of acetaminophen (APAP)-induced acute liver injury. Immunofluorescence analysis revealed that CRX-527-induced proliferative activity was predominantly observed in zone 2. Mechanistically, CRX-527 acts via TLR4 to induce transient IL-6 secretion, which subsequently activates the JAK2\/STAT3 signaling pathway. In addition, metabolomic profiling identified taurochenodeoxycholic acid (TCDCA) as a synergistic partner of IL-6 in promoting hepatocyte proliferation. In APAP-injured mice, treatment with CRX-527 alone or in combination with IL-6 and TCDCA significantly reduced hepatic necrosis, accelerated tissue repair, and improved survival. Collectively, our findings uncover a previously unrecognized combined effect between IL-6\/JAK2\/STAT3 signaling and TCDCA in promoting hepatocyte proliferation and highlight CRX-527 and the IL-6\/TCDCA combination as potential regenerative targets that warrant further preclinical evaluation for drug-induced liver injury, particularly in the setting of APAP overdose.<\/jats:p>","DOI":"10.3390\/biology15191725","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:19:08Z","timestamp":1790842748000},"page":"1725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological TLR4 Activation Promotes Hepatocyte Proliferation and Liver Repair Through Coordinated IL-6 and TCDCA Signaling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7737-0423","authenticated-orcid":false,"given":"Xinlu","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Cell Biology, College of Basic Medical Science, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Haoxin","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, College of Basic Medical Science, Naval Medical University, Shanghai 200433, 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