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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liver fibrosis may lead to cirrhosis and even cancer without effective clinical medicine available. Previous studies demonstrated that galactan-containing pectins or pectin-like polysaccharides might target Galectin-3 (Gal-3) to impede fibrosis. This research aims to discover novel pectin-like galactan to interfere with fibrosis for potential new drug development. Thus, we purify a novel homogeneous Rhamnogalacturonan-I like polysaccharide with galactan input, XHH2, from the Crocus sativus flower. XHH2 (MW: 35.7 kDa) consists of rhamnose, galacturonic acid, galactose, and arabinose in ratios of 6.6: 6.1: 25.2: 12.1. The backbone of XHH2 comprises 1, 3, 6-Gal and 1, 3, 4-GalA, with branches at O-3 of 1, 3, 6-Gal and O-4 of 1, 3, 4-GalA. O-3 branches include 1, 3-Gal, 1, 4-Gal, 1, 6-Gal, T-Gal, and T-Glc, while O-4 branches consist of 1, 2, 4-Rha, 1, 4-GalA, 1, 5-Ara, T-Ara, T-Gal, and T-α-HexA. Surface plasmon resonance measurement shows that XHH2 binds to both Gal-3 and integrin β1 to block Gal-3/integrin β1 interaction. Mechanism studies further suggest that XHH2 inactivates hepatic stellate cells (HSCs) via disturbing the Gal-3/Integrin-β1/FAK pathway to alleviate liver injury and fibrosis in vitro & in vivo. XHH2 shows a favorable drug safety in the acute toxicity test of oral administration of XHH2 in mice. Overall, XHH2 is an active ingredient against liver fibrosis by targeting the interaction between Gal-3 and Integrin-β1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Aims: Multiple studies have shown that hepatic fibrosis, a progressive condition that represents the endpoint of various chronic liver diseases, is primarily marked by the extensive activation of hepatic stellate cells (HSCs). However, the exact impact of cystic fibrosis transmembrane conductance regulator (CFTR) on HSCs during the development of hepatic fibrosis remains unclear., Methods: In our study, we measured CFTR levels in tissue samples and in HSCs activated by TGF-β stimulation. We established mouse models of liver fibrosis using carbon tetrachloride (CCl 4 ) and bile duct ligation (BDL). In vitro, we investigated the specific mechanisms of CFTR action in HSCs by exploring aggrephagy. We employed co-immunoprecipitation (co-IP) experiments to identify potential downstream targets of CFTR. Finally, through rescue experiments, we examined the impact of GTPase-activating protein - binding protein 1 (G3BP1) on CFTR-mediated activation of hepatic stellate cells., Result: In activated HSCs induced by TGF-β, the reduction of CFTR, various liver fibrosis models, and fibrotic tissue samples were identified. In vitro functional experiments confirmed that CFTR promoted the expression of fibrosis-related markers and aggrephagy in HSCs. Mechanistically, we found that CFTR directly interacts with G3BP1, thereby further promoting the TGF-β/Smad2/3 pathway. The inhibition of G3BP1 caused by CFTR knockdown reduced extracellular matrix deposition, contributing to alleviating liver fibrosis., Conclusion: We emphasize that CFTR activates aggrephagy and promotes HSC activation and hepatic fibrosis by targeting G3BP1, participating in the TGF-β/Smad2/3 signaling pathway. Overall, CFTR has been identified as a potential therapeutic target for liver fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)