Eriocitrin ameliorates hepatic fibrosis and inflammation: The involvement of PPARα-mediated NLRP1/NLRC4 inflammasome signaling cascades

Citri Reticulatae Pericarpium (Chenpi) is a traditional Chinese medicine and recorded to have hepatoprotective therapeutic and condition value. Eriocitrin (ER) a natural compound isolated from Citri Reticulatae Pericarpium may ameliorate hepatic inflammation in chronic liver diseases. The current study investigates the hepatoprotective effect and potential mechanism of ER against hepatic fibrosis. The hepatic fibrosis mouse model was constructed by intraperitoneally injecting thioacetamide (TAA) for five weeks. Hepatic stellate cells (HSCs) were treated with transforming growth factor-β (TGF-β). Meanwhile, lipopolysaccharide/adenosine triphosphate (LPS/ATP) was given to excite the normal mouse bone marrow-derived macrophages (BMDMs), and thus the cells could acquire the conditioned medium. Moreover, LX-2 cells were administrated with PPARα knockdown vector (siRNA-PPARα). RNA sequencing studies revealed that in mice induced by TAA, the PPARα/NOD-like receptor/neutrophil extracellular traps (NETs) significantly influence ER-based hepatic protection. In TAA-induced mice, ER could up-regulate PPARα and down-regulate NLRP1/NLRC4 and the development of NETs. Our findings indicated that ER significantly up-regulated PPARα, inhibited NLRP1/NLRC4 inflammasome in HSCs. Deficiency of PPARα in the activated LX-2 weakened the regulatory effect of ER on inhibiting the NLRP1/NLRC4 inflammasome. In addition, ER might hinder the activation of BMDMs and also obstruct IL-1β and IL-6 passage in the extracellular space. The results indicated that ER decreased inflammation by controlling the PPARα-NLRP1/NLRC4 signaling pathway and inhibiting fibril formation. Collectively, our results underscore the therapeutic potential of ER in addressing hepatic fibrosis. [Display omitted] •Eriocitrin regulates macrophage-hepatic stellate cells crosstalk in hepatic fibrosis.•Eriocitrin attenuates hepatic fibrosis and inflammation response by regulating PPARα-NLRP1/NLRC4 signaling pathway.•Eriocitrin reduced the infiltration of immune cells via inhibiting the formation of NETs.