The activation of TLR4-MyD88 signaling promotes hepatic dysfunction and fibrotic changes in SD rats resulting from prolonged exposure to sodium arsenite.

[Display omitted] • Arsenite exposure leads to upregulation of TLR4-MyD88 signaling in rats liver. • The natural ligand LPS enhances TLR4-MyD88 signaling, resulting in liver fibrosis and dysfunction in rats. • The activation of TLR4-MyD88 signaling in the liver of arsenite-exposed rats can be effectively blocked by TAK-242, a specific inhibitor targeting TLR4. • TAK-242 intervention effectively mitigates arsenite-induced fibrotic alterations and dysfunction in rats liver chronically exposed to arsenite. Arsenic, a poisonous metalloid element, is linked to liver diseases, but the exact mechanisms for this process are not yet to be completely elucidated. Toll like receptor 4 (TLR4), acting as a pathogenic pattern recognition receptor, plays a pivotal role in various inflammatory diseases via the myeloid differentiation factor 88 (MyD88) pathway. This study aims to investigate the involvement of the TLR4-MyD88 signaling pathway in liver injury induced by prolonged exposure to sodium arsenite (NaAsO 2) in Sprague-Dawley rats. Our research findings demonstrate the activation of TLR4-MyD88 signaling pathway in long-term NaAsO 2 -exposed rat liver tissues, leading to a significant release of inflammatory factors, which suggests its potential involvement in the pathogenesis of NaAsO 2 -induced liver injury. We further administered lipopolysaccharide (LPS), a natural ligand of TLR4, and TAK-242, a specific inhibitor of TLR4, to rats in order to validate the specific involvement of the TLR4-MyD88 signaling pathway in NaAsO 2 -induced liver injury. The results showed that, 1 mg/kg.bw LPS treatment significantly activated TLR4-MyD88 signalling pathway and its mediated pro-inflammatory factors, leading to up-regulation of activation indicators in hepatic stellate cells (HSCs) as well as increased secretion levels of extracellular matrix (ECM) in the liver, and ultimately induced liver fibrosis and dysfunction in rats. Relevantly, subsequent administration of 0.5 mg/kg.bw TAK-242 significantly attenuated the expression levels of TLR4 and its associated proteins, mitigated collagen deposition, and partially improved liver fibrosis and dysfunction caused by NaAsO 2 in rats. Our study fully confirms the pivotal role of the TLR4-MyD88 signaling in promoting liver injury induced by NaAsO 2 , thereby providing a novel molecular target for preventing and treating patients with arsenic poisoning-related liver injury. [ABSTRACT FROM AUTHOR]