Pharmacological TLR4 Activation Promotes Hepatocyte Proliferation and Liver Repair Through Coordinated IL-6 and TCDCA Signaling

The regenerative capacity of the liver is frequently insufficient following severe injury, and effective therapeutic strategies remain limited. 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.