Syringin attenuates fibrogenesis and inflammation through SIRT3-regulated P2X7 receptor signaling pathway in hepatic fibrosis

Hepatic fibrosis manifests with impaired extracellular matrix (ECM) deposition and inflammation within the liver. This study probes deep into the hepatoprotective effects and underlying mechanisms of syringin (SY) against hepatic fibrosis and inflammation.

A model of hepatic fibrosis in mice was established through intraperitoneal injection of thioacetamide (TAA) and silencing of SIRT3. RNA sequencing was employed to elaborate upon the SY-associated signaling network. Hepatic stellate cells (HSCs) were treated with transforming growth factor-beta (TGF-β) and lipopolysaccharide/adenosine triphosphate (LPS/ATP) was utilized to induce bone marrow-derived macrophages (BMDMs) for conditioned medium collection. To comprehensively assess the role of SIRT3 in SY-mediated effects, LX-2 cells and BMDMs underwent SIRT3 knockdown (siRNA-SIRT3).

RNA sequencing analysis suggested that SY exerts its hepatoprotective effects primarily through modulation of the SIRT3/NOD-like receptor pathway. After knocking down SIRT3 via shRNA, the protein and mRNA levels of P2×7r in mouse livers increased significantly, and inflammation was exacerbated. Furthermore, SY up-regulated SIRT3 protein expression while down-regulating PINK1 and Parkin, suggesting a role in mitochondrial quality control. In particular, SIRT3 deficiency in LX-2 cells and BMDMs attenuated SY's regulatory effects on ECM remodeling and inflammation. SY also inhibited BMDM activation, thereby lessening the extracellular release of IL-1β and IL-18.

Collectively, the above-summarized results suggest that SY mitigates hepatic inflammation and fibrogenesis by modulating the SIRT3-P2×7r/NLRP3 signaling axis, positioning it as a prospective therapeutic alternative for hepatic fibrosis. SY might be a prospective therapeutic candidate, and its mechanism would be a new direction or strategy for hepatic fibrosis.