Simvastatin inhibits hepatic stellate cells activation by regulating the ferroptosis signaling pathway

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2023-10, Vol.1869 (7), p.166750-166750, Article 166750
• Main Authors: Kitsugi, Kensuke, Noritake, Hidenao, Matsumoto, Moe, Hanaoka, Tomohiko, Umemura, Masahiro, Yamashita, Maho, Takatori, Shingo, Ito, Jun, Ohta, Kazuyoshi, Chida, Takeshi, Suda, Takafumi, Kawata, Kazuhito
• Format: Article
• Language: English
• Subjects: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors; Glutathione peroxidase 4; Liver fibrosis; Mevalonic acid; Nonalcoholic steatohepatitis
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2023.166750

Ferroptosis is a form of regulated cell death and its promotion in hepatic stellate cells (HSCs) attenuates liver fibrosis. Statins, which are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may induce ferroptosis via the downregulation of glutathione peroxidase 4 (GPX4) by inhibiting the mevalonate pathway. However, little evidence is available regarding the association between statins and ferroptosis. Therefore, we investigated the association between statins and ferroptosis in HSCs. Two human HSC cell lines, LX-2 and TWNT-1, were treated with simvastatin, an HMG-CoA reductase inhibitor. Mevalonic acid (MVA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were used to determine the involvement of the mevalonate pathway. We performed a detailed analysis of the ferroptosis signaling pathway. We also investigated human liver tissue samples from patients with nonalcoholic steatohepatitis to clarify the effect of statins on GPX4 expression. Simvastatin reduced cell mortality and inhibited HSCs activation, accompanied by iron accumulation, oxidative stress, lipid peroxidation, and reduced GPX4 protein expression. These results indicate that simvastatin inhibits HSCs activation by promoting ferroptosis. Furthermore, treatment with MVA, FPP, or GGPP attenuated simvastatin-induced ferroptosis. These results suggest that simvastatin promotes ferroptosis in HSCs by inhibiting the mevalonate pathway. In human liver tissue samples, statins downregulated the expression of GPX4 in HSCs without affecting hepatocytes. Simvastatin inhibits the activation of HSCs by regulating the ferroptosis signaling pathway. [Display omitted] •Simvastatin inhibited the activation of HSCs.•Simvastatin induced ferroptosis in HSCs.•Mevalonic acid attenuated the effects of simvastatin.•Statin downregulated GPX4 expression in HSCs in vivo.