Sodium aescinate induces renal cell ferroptosis through the ATF4/CTH/SQOR axis.

Sodium aescinate (SA), derived from seeds of the Chinese herb Suoluozi (Aesculus wilsonii Rehd.), has been linked to severe kidney injury during clinical use. We previously found that SA induces nephrocyte ferroptosis, and upregulation of glutathione peroxidase 4 (GPX4) or ferroptosis suppressor protein 1 (FSP1) expression only partially attenuates this toxic effect. In this study, we demonstrated that SA reduced cellular levels of hydrogen sulfide (H2S) and reduced coenzyme Q10 (CoQ10H2), leading to impaired antioxidant defense and lipid peroxidation (LPO) in renal cells. Mechanistically, SA suppressed the expression of activating transcription factor 4 (ATF4), cystathionine γ-lyase (CTH) and sulfide: quinone oxidoreductase (SQOR). The SA-induced downregulation of CTH expression was attributed to the decreased recruitment of ATF4 to the cis-regulatory element (CRE) of the CTH promoter. ATF4 overexpression in SA-treated cells upregulated CTH expression, which elevated H2S and CoQ10H2 levels, improved antioxidant defense, and reduced ferroptosis. Critically, CTH silencing completely abrogated these protective effects. Conversely, CTH or SQOR overexpression, or H2S supplementation restored CoQ10H2 levels and protected against SA-induced ferroptosis. However, in SQOR-deficient cells, neither intervention rescued CoQ10H2 nor alleviated nephrotoxicity despite increased H2S levels. Additionally, alternative oxidase (AOX) overexpression abolished the protective effect of the ATF4/CTH/SQOR axis by oxidizing CoQ10H2 back to its inactive form. In conclusion, SA induced ferroptosis-mediated kidney injury by disrupting the ATF4/CTH/SQOR axis, leading to reduced CoQ10H2 levels and impaired redox homeostasis. This study introduces this pathway as a novel therapeutic target for SA-induced nephrotoxicity.