Germacrone protects renal tubular cells against ferroptotic death and ROS release by re-activating mitophagy in diabetic nephropathy

ABSTRACTMitophagy is a critical intracellular event during the progression of diabetic nephropathy (DN). Our previous study demonstrated that germacrone has anti-ferroptotic properties and is a potential therapeutic agent for DN. However, the relationship among germacrone, mitophagy, and ferroptosis in DN remains unclear. In this study, the data confirmed that germacrone ameliorates high glucose (HG)-induced ferroptosis through limiting Fe (2+) content and lipid reactive oxygen species (ROS) accumulation in human kidney 2 (HK-2) cells. Germacrone reversed HG-mediated inhibition of mitophagy. Mitophagy inhibition and anabatic mitochondrial ROS abrogate germacrone-mediated protective effects against ferroptotic death, resulting in the subsequent activation of mitochondrial DNA (mtDNA) cytosolic leakage-induced stimulator of interferon response CGAMP interactor 1 (STING) signaling. The combination of a mitochondrial ROS antagonist and germacrone acts synergistically to alleviate the ferroptotic death of tubular cells and DN symptoms. In summary, germacrone ameliorated ferroptotic death in tubular cells by reactivating mitophagy and inhibiting mtDNA-STING signaling in DN. This study provides a novel insight into germacrone-mediated protection against DN progression and further confirms that antioxidant pharmacological strategies facilitate the treatment of DN.KEYWORDS: Germacroneferroptosismitophagydiabetic nephropathySTINGDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Additional informationFundingThis research was funded by the Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (2022ZB273), Cultivation Program for Excellent Young Talents of Hangzhou First People’s Hospital (YQNYC202131), Zhejiang Province Chinese Medicine Modernization Program (2020ZX001), The Key Project of Scientific Research Foundation of Chinese Medicine (2022ZZ002), the "Pioneer" and "Leading Goose" R&D Program of Zhejiang (2022C03118), the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (LHDMZ22H050001), The Key project of Basic Scientific Research Operating Funds of Hangzhou Medical College (KYZD202002).