Cordycepin Suppressed Ferroptosis to Ameliorate Acute Kidney Injury Through Inhibiting the DNMT1/KLF15/FTH1 Axis

Cordycepin (COR) alleviated acute kidney injury (AKI) by hindering ferroptosis, although its exact mechanism was unclear. In the current research, we sought to explore whether COR mitigated AKI by impacting Krüppel-like factor 15 (KLF15) and to probe the specific regulatory mechanisms. KLF15 on the ferritin heavy chain 1 (FTH1) promoter was predicted by the JASPAR database and validated via ChIP and Dual-luciferase reporter assay. Differential gene expression in AKI was analyzed based on the GSE212678 dataset. The CpG island in the KLF15 promoter was forecasted via the MethPrimer database. CCK-8 was utilized to assay the cellular viability. Flow cytometry was utilized to verify the lipid peroxidation level. C57BL/6J mice were subjected to bilateral renal ischemia-reperfusion injury to induce AKI and injected with COR via the tail vein. HE staining was performed for histological detection. The Fe²⁺, serum creatinine (Scr), and blood urea nitrogen (BUN) were examined using the colorimetric assay kit. The mRNA and protein levels were checked by RT-qPCR, western blot, and IHC. The overexpression of KLF15 activated FTH1 transcription in AKI. COR attenuated ferroptosis in H/R-exposed HK-2 cells through activated KLF15-mediated transcription of FTH1. DNMT1 enhanced the KLF15 promoter methylation to repress its expression, which induced ferroptosis in AKI. COR activated the KLF15/FTH1 axis by repressing DNMT1 expression, which impeded ferroptosis in HK-2 cells after H/R. COR suppressed ferroptosis by regulating the DNMT1/KLF15/FTH1 axis, thereby improving AKI in vivo. COR suppressed ferroptosis in AKI by depressing DNMT1/KLF15/FTH1 axis.