Asarinin alleviates hepatic fibrosis through TRα-STAT3 pathway: A new strategy by regulating liver microenvironment

Ethnopharmacological relevance Asarum heterotropoides F. Schmidt, a classic Chinese herb, traditionally treats liver deficiency with its pungent, warm nature and liver-qi smoothing properties. Asarinin (ASA), an abundant and characteristic lignan in Asarum, has the potential to protect the liver and has shown measurable systemic exposure in the body, making it a key candidate for verifying this traditional use. Aim of the study We aim to delineate the molecular mechanisms underlying the hepatoprotective activity of ASA. Materials and methods Liver injury and fibrosis was generated in C57BL/6 mice by intraperitoneal TAA and CCL 4 , with oral ASA treatment. To investigate the mechanisms, neutrophil depletion and TRα knockdown approaches were employed. LX-2 were activated using TGF-β and co-cultured by ASA, neutrophils, and/or conditioned medium from primary hepatocytes; TRα was silenced via siRNA. Results The findings indicate that ASA alleviates hepatic fibrosis by reducing extracellular matrix deposition, inflammation, EMT, and neutrophil extracellular traps through TRα-STAT3 signaling pathway. Loss of TRα exacerbates fibrotic progression, whereas neutrophil ablation attenuates pathology. In vitro , ASA modulates ECM composition, inflammatory cytokine levels, and EMT-related processes in activated hepatic stellate cells. These effects are mediated through TRα and STAT3 signaling, as TRα knockdown diminishes the regulatory influence of ASA on LX-2 activation. RNA sequencing was used to verify the relevant mechanisms. ASA exerts potent anti-fibrotic effects by disrupting intercellular crosstalk and modulating the TRα-STAT3 signaling axis. Conclusions The therapeutic efficacy of ASA against liver fibrosis may hinge on its ability to target TRα-dependent STAT3 activation, thereby reshaping the hepatic microenvironment.