Objective <p>Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) is a crucial anti-apoptotic protein; however, its role and associated molecular pathways in ferroptosis remain largely unexplored. This study aimed to investigate the effects of CIAPIN1 on ferroptosis in lipopolysaccharide (LPS)-induced podocytes and the associated underlying phenomenon.</p> Methods <p>In this study, we recruited 50 sepsis patients (aged 56.63 ± 10.33) with acute kidney injury (AKI), 50 sepsis patients without AKI, and 50 healthy controls. We established an in vitro model of LPS-induced MPC5 podocytes. RT-qPCR and Western blotting were used to evaluate mRNA and protein expression, respectively.</p> Results <p>Serum CIAPIN1 is downregulated in patients with septic AKI and LPS-induced podocytes. CIAPIN1 overexpression (OE-CIAPIN1) attenuated cell proliferation and apoptosis in LPS-induced podocytes. OE-CIAPIN1 elevated phosphorylated phosphoinositide 3-kinase (p-PI3K; p85, Tyr458) and phosphorylated protein kinase B (p-Akt; Ser473) levels in LPS-induced podocytes. OE-CIAPIN1 significantly elevated synaptopodin mRNA levels and remarkably lowered desmin mRNA expression in MPC5 cells. In contrast, treatment with the PI3K/Akt pathway inhibitor, LY294002, reversed synaptopodin and desmin mRNA expression in MPC5 cells. Additionally, OE-CIAPIN1 reduced the malondialdehyde (MDA) content and Fe2 + concentration in the lysate of MPC5 cells, while elevating the MDA content and Fe2 + concentration by LY294002 treatment. Furthermore, OE-CIAPIN1 increased ferroptosis-related proteins, including solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), in MPC5 cells, which was reversed by LY294002 treatment.</p> Conclusion <p>These results suggest that serum CIAPIN1 inhibits LPS-induced ferroptosis in podocytes by regulating the PI3K/AKT signaling pathway.</p>