Exertional heat stroke induces liver injury through the activation of the TLR4/NF-κB signaling pathway
- 1Fuzong Clinical Medical College, Fujian Medical University, No. 156 Xierhuan North Road, Gulou District, Fuzhou, Fujian, 350025, China
- 2Department of Hepatobiliary Diseases, 900th Hospital of PLA (The 900th Hospital of the Joint Logistics Support Force of PLA), No. 156 Xierhuan North Road, Gulou District, Fuzhou, Fujian, 350025, China
- 3Department of Gastroenterology, Central Theater General Hospital, No. 627 Wuluo Road, Wuchang District, Wuhan, Hubei, 430070, China
Abstract
Background: Exertional heat stroke (EHS) disrupts the intestinal barrier and facilitates lipopolysaccharide (LPS) translocation, thereby activating hepatic inflammatory signaling pathways and contributing to liver injury. This study aimed to investigate the role and mechanism of the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway in EHS-induced liver injury.
Methods: An EHS Sprague-Dawley rat model was developed through treadmill running, with EHS defined as achieving a core temperature of 42.9°C ± 0.1°C. The model rats were pretreated with either TAK-242 (10.0 mg/kg), a TLR4 inhibitor or saline prior to running. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry, and Western blot (WB) analyses were performed to investigate the expression of the TLR4/NF-κB pathway in the liver and the tight junction proteins in the intestine. HepG2 cells under heat stress and LPS exposure were utilized to examine TLR4/NF-κB activation at transcriptional and protein levels.
Results: EHS rats exhibited significantly increased liver inflammation and elevated levels of ALT (Alanine Aminotransferase), AST (Aspartate Aminotransferase), TNF-α (Tumor Necrosis Factor-α), IL-1β (Interleukin-1β), and IL-6 (Interleukin-6) compared to the normal control group (all P < 0.05). There was a reduction in intestinal occludin, Zonula occludens-1 (ZO-1), E-cadherin and an increase in serum LPS levels, and upregulation of hepatic TLR4/NF-κB signaling (all P < 0.05). Pretreatment with TAK-242 reduced hepatic TLR4/NF-κB signaling and inflammation both in vivo and in vitro. However, it did not significantly restore occludin, ZO-1, and E-cadherin expression levels in EHS rats.
Conclusions: EHS leads to liver injury through the activation of the TLR4/NF-κB signaling pathway. TAK-242 pretreatment attenuates liver inflammation by downregulating the TLR4/NF-κB signaling, supporting a mechanistic role for this pathway in EHS-induced liver injury.
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BibTeX
@article{teng2026exertional,
title = {{Exertional heat stroke induces liver injury through the activation of the TLR4/NF-κB signaling pathway}},
author = {Long Teng and Haicong Wu and Fangze Cai and Meiyan Wang and Qingqing Lin and Li Chen and Xin Chang and Dongliang Li and Xiaoling Zhou},
journal = {Biochemistry and Biophysics Reports},
year = {2026},
month = oct,
doi = {10.1016/j.bbrep.2026.102836},
url = {https://doi.org/10.1016/j.bbrep.2026.102836},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exertional heat stroke induces liver injury through the activation of the TLR4/NF-κB signaling pathway
AU - Long Teng
AU - Haicong Wu
AU - Fangze Cai
AU - Meiyan Wang
AU - Qingqing Lin
AU - Li Chen
AU - Xin Chang
AU - Dongliang Li
AU - Xiaoling Zhou
PY - 2026
DA - 2026/10/17
JO - Biochemistry and Biophysics Reports
DO - 10.1016/j.bbrep.2026.102836
UR - https://doi.org/10.1016/j.bbrep.2026.102836
AB - Background: Exertional heat stroke (EHS) disrupts the intestinal barrier and facilitates lipopolysaccharide (LPS) translocation, thereby activating hepatic inflammatory signaling pathways and contributing to liver injury. This study aimed to investigate the role and mechanism of the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway in EHS-induced liver injury. Methods: An EHS Sprague-Dawley rat model was developed through treadmill running, with EHS defined as achieving a core temperature of 42.9°C ± 0.1°C. The model rats were pretreated with either TAK-242 (10.0 mg/kg), a TLR4 inhibitor or saline prior to running. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry, and Western blot (WB) analyses were performed to investigate the expression of the TLR4/NF-κB pathway in the liver and the tight junction proteins in the intestine. HepG2 cells under heat stress and LPS exposure were utilized to examine TLR4/NF-κB activation at transcriptional and protein levels. Results: EHS rats exhibited significantly increased liver inflammation and elevated levels of ALT (Alanine Aminotransferase), AST (Aspartate Aminotransferase), TNF-α (Tumor Necrosis Factor-α), IL-1β (Interleukin-1β), and IL-6 (Interleukin-6) compared to the normal control group (all P < 0.05). There was a reduction in intestinal occludin, Zonula occludens-1 (ZO-1), E-cadherin and an increase in serum LPS levels, and upregulation of hepatic TLR4/NF-κB signaling (all P < 0.05). Pretreatment with TAK-242 reduced hepatic TLR4/NF-κB signaling and inflammation both in vivo and in vitro. However, it did not significantly restore occludin, ZO-1, and E-cadherin expression levels in EHS rats. Conclusions: EHS leads to liver injury through the activation of the TLR4/NF-κB signaling pathway. TAK-242 pretreatment attenuates liver inflammation by downregulating the TLR4/NF-κB signaling, supporting a mechanistic role for this pathway in EHS-induced liver injury.
SN - 2405-5808
ER -