This investigation explored the hepatoprotective capabilities of Bruceine A (BA) and its underlying mechanisms in mitigating hepatic fibrosis. Hepatic stellate cells (HSCs) and mouse primary hepatocytes were treated with TGF-β and subsequently exposed to BA. To assess the effects of BA on the NR2F2-HMGB1 signaling cascade, these cells underwent transfection with a siRNA vector targeting NR2F2. The interaction between NR2F2 and the HMGB1 promoter was elucidated using a dual luciferase assay. In vivo, C57BL/6 mice were treated with thioacetamide (TAA) to induce liver damage, followed by administration of BA. The study found that BA moderated extracellular matrix (ECM) buildup, epithelial-mesenchymal transition (EMT), and inflammatory mediator levels, while concurrently reducing NR2F2 and HMGB1 expression in activated HSCs. Furthermore, BA lessened pyroptosis in hepatocytes, curtailing the inflammatory response. The absence of NR2F2 in HSCs or hepatocytes hindered BA's inhibitory effect on this pathway. It was demonstrated that NR2F2 binds directly to the HMGB1 promoter. Treatment with BA resulted in diminished serum levels of ALT and AST, mitigated damage in hepatic tissues, and decreased the ECM and neutrophil extracellular traps (NETs), thus protecting hepatocytes from fibrosis. Furthermore, BA suppressed the synthesis of inflammatory mediators such as NLRP3, caspase-1, and IL-1β by blocking the NR2F2-driven HMGB1 pathway, markedly reversing hepatic fibrosis. These observations highlight the efficacy of BA as a viable therapeutic candidate for hepatic fibrosis.
Keywords: Bruceine A; HMGB1; Hepatic fibrosis; Inflammation; NR2F2.
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