Protopine attenuates hepatic fibrosis via HDAC6-mediated NLRP3 inflammasome activation.

Hepatic fibrosis is a central pathological feature of chronic liver diseases, but effective pharmacological interventions remain limited. Protopine (PTP), a naturally isoquinoline alkaloid compound, has been reported to exhibit anti-inflammatory and hepatoprotective properties. However, its specific role and mechanisms in hepatic fibrosis remain unclear. This study employed a CCl4-induced murine model and a TGF-β1-stimulated LX-2 cell model to investigate the therapeutic effects and molecular mechanisms of PTP in hepatic fibrosis. The results demonstrated that PTP significantly alleviated liver injury and collagen deposition, suppressed hepatic stellate cell (HSC) activation and restored extracellular matrix (ECM) homeostasis. Mechanistically, PTP directly binds to histone deacetylase 6 (HDAC6) and downregulated the expression of NLRP3 and α-SMA at the mRNA and protein levels, reducing the secretion of downstream pro-inflammatory factors IL-1β and IL-18. Further use of an HDAC6 inhibitor confirmed the consistent effect with PTP. These findings reveal that PTP exerts anti-fibrotic effects through the HDAC6-NLRP3 signaling axis, providing a theoretical basis for its development as a lead compound for the treatment of hepatic fibrosis.