BACKGROUND: Severe renal ischemia and reperfusion injury (IRI) progresses to renal interstitial fibrosis (RIF) with limited therapeutic strategies. Although ferrptosis and macrophage polarization both play important roles in this model, their specific pathogenesis and interactions have not been elucidated. Therefore, we aimed to explore the mechanisms by which ferrotosis occurs in renal tubular epithelial cells (RTECs) and ferroptotic cell-derived exosomes induce macrophage polarization in IRI-related RIF model. RESULT: Compared with the sham group, the IR group showed more severe kidney injury in HE staining, more collagen fibers in Masson staining, and higher α-SMA expression levels in immunohistochemistry. Total iron and MDA content increased while GSH content decreased. The IR group had more significant mitochondrial damage and higher PTGS2 and TFRC mRNA levels than those in the sham group. Compared with the IR group, the above indexes were all alleviated in the IR+Fer-1 or IR+ATF3 CONCLUSION: ATF3 might accelerate the ferroptosis by inhibiting Nrf2/ARE pathway, and exosomes from ferroptotic cells reduced the M1/M2 macrophage ratio, promoting fibrosis.