M1 Macrophage Exosomes Induce Ferroptosis via MiR-582-5p-Mediated ZBTB10 Suppression in Sepsis-Induced Acute Kidney Injury

Introduction Sepsis-induced acute kidney injury (S-AKI) poses a significant clinical challenge, necessitating effective therapeutic strategies. This study investigates the influence of M1-polarized macrophage-derived exosomes on the proliferation and ferroptosis of renal tubular epithelial cells (HK2). Material and methods We polarized THP-1 and RAW264.7 cells to the M1 phenotype and validated their polarization through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Exosomes isolated from these macrophages were applied to treat HK2 cells, resulting in a significant reduction in cell proliferation, as demonstrated by cell counting kit-8 (CCK-8) and 5-ethynyl-2’deoxyuridine (EdU) assays. Furthermore, increased malondialdehyde (MDA) and Fe2+ levels, decreased glutathione (GSH) levels, and altered mitochondrial morphology indicated enhanced ferroptosis. RT-qPCR and Western blot analyses showed upregulation of the ferroptosis-promoting gene TFR1, while other related genes remained unaffected. Results We identified miR-582-5p as a key exosomal miRNA significantly upregulated in HK2 cells following treatment with M1-polarized macrophage exosomes. Overexpression of miR-582-5p in HK2 cells mirrored the exosomal effects, inhibiting proliferation and promoting ferroptosis. Mechanistic studies revealed that miR-582-5p binds to the 3’ untranslated region (UTR) of ZBTB10, suppressing its expression. This suppression led to increased H3K27ac modification of the TFR1 promoter, enhancing TFR1 transcription and ferroptosis. Conclusions In conclusions, these findings uncover a novel pathway by which M1 macrophage exosomes deliver miR-582-5p to induce ferroptosis in HK2 cells, highlighting potential therapeutic targets for S-AKI.