Pharmacological TLR4 Activation Promotes Hepatocyte Proliferation and Liver Repair Through Coordinated IL-6 and TCDCA Signaling.
- 1Department of Cell Biology, College of Basic Medical Science, Naval Medical University, Shanghai 200433, China.
- 2Department of Health Toxicology, Naval Medical University, Shanghai 200433, China.
- 3Shanghai Key Laboratory of Cell Engineering, Naval Medical University, Shanghai 200433, China.
Abstract
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.
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BibTeX
@article{yu2026pharmacological,
title = {{Pharmacological TLR4 Activation Promotes Hepatocyte Proliferation and Liver Repair Through Coordinated IL-6 and TCDCA Signaling.}},
author = {Xinlu Yu and Haoxin Ma and Chao Wang and Ke Feng and Pingxin Sun and Jiqianzhu Zhang and Junyu Lu and Hongxia Zhang and Chao Wang and Chunyan Wang and Haiying Zhu and Wenlin Li},
journal = {Biology},
year = {2026},
month = oct,
doi = {10.3390/biology15191725},
url = {https://europepmc.org/article/MED/42883397},
note = {CC BY},
}
RIS
TY - JOUR
TI - Pharmacological TLR4 Activation Promotes Hepatocyte Proliferation and Liver Repair Through Coordinated IL-6 and TCDCA Signaling.
AU - Xinlu Yu
AU - Haoxin Ma
AU - Chao Wang
AU - Ke Feng
AU - Pingxin Sun
AU - Jiqianzhu Zhang
AU - Junyu Lu
AU - Hongxia Zhang
AU - Chao Wang
AU - Chunyan Wang
AU - Haiying Zhu
AU - Wenlin Li
PY - 2026
DA - 2026/10/01
JO - Biology
DO - 10.3390/biology15191725
UR - https://europepmc.org/article/MED/42883397
AB - 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.
SN - 2079-7737
ER -