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Background Liver fibrosis is a pathological wound-healing response caused by chronic liver damage. Mitochondria regulate hepatic energy metabolism and oxidative stress. Accumulating evidence has revealed that increased mitochondrial oxidative stress contributes to the activation of fibrogenesis. However, the roles and underlying mechanisms of mitochondrial oxidative stress in liver fibrosis remain unknown. Methods and results In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8 weeks. Furthermore, intervention experiments were achieved by CCl4 combined with the intraperitoneal injection of mitoquinone mesylate (mitoQ). We demonstrated that the chronic CCl4 exposure resulted in severe hepatic fibrogenesis and significantly promoted the production of reactive oxygen species (ROS) and mitochondrial abnormalities. Besides, JNK/YAP pathway was also activated. By contrast, the administration of mitoQ markedly inhibited the expression of pro-fibrogenic transforming growth factor-β as well as type I collagen. The antifibrotic effects of mitoQ were also confirmed by hematoxylin and eosin staining and Sirius red staining. Moreover, mitoQ substantially reduced CCl4-induced mitochondrial damage and the release of ROS. Further studies suggested that this protection against liver fibrosis was mechanistically related to the inhibition of phosphorylation of JNK and the nuclear translocation of YAP. Conclusion In conclusion, these findings revealed that mitoQ attenuated liver fibrosis by inhibiting ROS production and the JNK/YAP signaling pathway. Selective targeting JNK/YAP may serve as a therapeutic strategy for retarding progression of chronic liver disease.

Chronic acrylamide (ACR) intoxication causes typical pathology of axon degeneration. Moreover, sterile‐α and toll/interleukin 1 receptor motif‐containing protein 1 (SARM1), the central executioner of the programmed axonal destruction process under various insults, is up‐regulated in ACR neuropathy. However, it remains unclear whether inhibitors targeting SARM1 are effective or not. Among all the pharmacological antagonists, berberine chloride (BBE), a natural phytochemical and the first identified non‐competitive inhibitor of SARM1, attracts tremendous attention. Here, we observed the protection of 100 μM BBE against ACR‐induced neurites injury (2 mM ACR, 24 hr) in vitro, and further evaluated the neuroprotective effect of BBE (100 mg/kg p.o. three times a week for 4 weeks) in ACR‐intoxicated rats (40 mg/kg i.p. three times a week for 4 weeks). The expression of SARM1 was also detected. BBE intervention significantly inhibited the overexpression of SARM1, ameliorated axonal degeneration, alleviated pathological changes in the sciatic nerve and spinal cord, and improved neurobehavioral symptoms in ACR‐poisoned rats. Thus, BBE exhibits a strong neuroprotective effect against the SARM1‐dependent axon destruction in ACR neuropathy. Meanwhile, our study underscores the need for appropriate inhibitor selection in diverse situations that would benefit from blocking the SARM1‐dependent axonal destruction pathway.

Background Mitochondrial dynamics is essential for the maintenance of healthy mitochondrial network. Emerging evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of hepatic fibrogenesis following chronic liver injury. However, the role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in the context of liver fibrosis remains unclear. Methods and Results In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8 weeks. Furthermore, mitochondrial fission intervention experiments were achieved by the mitochondrial division inhibitor 1 (Mdivi-1). The results demonstrated that chronic CCl4 exposure resulted in severe hepatic fibrogenesis and mitochondrial damage. By contrast, pharmacological inhibition of mitochondrial division by Mdivi-1 substantially reduced the changes of mitochondrial dynamics and finally prevented the deposition of extracellular matrix proteins. Mechanistically, excessive mitochondrial fission may activate hepatic stellate cells through RIPK1-MLKL-dependent hepatocyte death, which ultimately promotes liver fibrosis. Conclusion Our study imply that inhibiting Drp1-mediated mitochondrial fission attenuates CCl4-induced liver fibrosis and may serve as a therapeutic target for retarding progression of chronic liver disease.

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