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.