Wang Zhilei, Liu Jingwen, Mou Yu, Zhou Xianglu, Liao Wenhao, Li Yuchen, Liu Yong, Tang Jianyuan
Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China.
Phytomedicine. 2025 Jul 25;143:156904. doi: 10.1016/j.phymed.2025.156904. Epub 2025 May 24.
Maintaining cholesterol homeostasis is crucial for sustaining human health and physiological function. Although the detrimental effects of chronic cholesterol overload on hepatic injury and fibrosis are well documented, the molecular mechanisms driving this pathology remain incompletely understood.
This study investigates the mechanistic role of chronic cholesterol overload in driving liver fibrosis and evaluates the therapeutic efficacy of honokiol as a targeted intervention.
High-cholesterol models induced by cholesterol and 25-hydroxycholesterol in human HepG2 cells or induced by cholesterol crystals in mouse bone marrow-derived macrophages were established. We also examined the effect of cholesterol on the livers of mice following a 20-week regimen of high-cholesterol diets.
Excess cholesterol interfered with normal cholesterol metabolism both in vitro and in vivo, and led to liver damage and fibrosis in vivo. Further research showed that cholesterol exposure triggered NLRP3 inflammasome activation and programmed cell death called pyroptosis; induced an increase in mitochondrial ROS and a disruption of intracellular redox homeostasis, followed by the opening of the mitochondrial permeability transition pore; and finally induced cellular DNA damage, resulting in the translocation of the double-stranded DNA fragment into the cytoplasm and the activation of the DNA-sensing adaptor STING. The activation of the NLRP3-cGAS-STING axis initiated the downstream cascade reaction and up-regulated the expression of pro-inflammatory cytokines, including IL-1β, TNF-α, and IFN-β, thus facilitating liver damage and fibrosis. Furthermore, honokiol, an active ingredient in Magnolia officinalis, could alleviate liver damage and fibrosis by blocking NLRP3 inflammasome activation, pyroptosis, and the cGAS-STING pathway.
Systematic evidence shows that cholesterol induces liver fibrosis through the activation of the NLRP3-cGAS-STING signaling axis and that honokiol demonstrates interventional efficacy in mitigating this process.
维持胆固醇稳态对于维持人类健康和生理功能至关重要。尽管慢性胆固醇过载对肝损伤和纤维化的有害影响已有充分记录，但驱动这种病理过程的分子机制仍未完全了解。
本研究探讨慢性胆固醇过载在驱动肝纤维化中的机制作用，并评估厚朴酚作为靶向干预措施的治疗效果。
建立了胆固醇和25-羟基胆固醇在人HepG2细胞中诱导的高胆固醇模型，或胆固醇晶体在小鼠骨髓来源巨噬细胞中诱导的高胆固醇模型。我们还研究了高胆固醇饮食20周方案对小鼠肝脏的影响。
过量胆固醇在体外和体内均干扰正常胆固醇代谢，并导致体内肝损伤和纤维化。进一步研究表明，胆固醇暴露触发NLRP3炎性小体激活和称为细胞焦亡的程序性细胞死亡；诱导线粒体ROS增加和细胞内氧化还原稳态破坏，随后线粒体通透性转换孔开放；最终诱导细胞DNA损伤，导致双链DNA片段易位到细胞质中并激活DNA传感衔接蛋白STING。NLRP3-cGAS-STING轴的激活启动了下游级联反应并上调了促炎细胞因子的表达，包括IL-1β、TNF-α和IFN-β，从而促进肝损伤和纤维化。此外，厚朴酚是厚朴中的一种活性成分，可通过阻断NLRP3炎性小体激活、细胞焦亡和cGAS-STING途径来减轻肝损伤和纤维化。
系统证据表明，胆固醇通过激活NLRP3-cGAS-STING信号轴诱导肝纤维化，厚朴酚在减轻这一过程中具有干预效果。
