Pharmacological inhibition of fatty acid-binding protein 4 alleviates sepsis-associated acute kidney injury in mice via suppressing ferroptosis

Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening clinical condition with limited therapeutic options, where ferroptosis serves as a key pathogenic driver. In this study, we conducted clinical sample analyses and proteomic profiling, and identified that fatty acid-binding protein 4 (FABP4) was significantly upregulated in the plasma of patients with SA-AKI, as well as in the renal tissues of SA-AKI model mice. To explore the functional role of FABP4, we administered BMS-309403 (BMS), a selective FABP4 inhibitor, in both a lipopolysaccharide (LPS)-induced murine SA-AKI model and an in vitro model of RAS-selective lethal 3 (RSL3)-treated human renal tubular epithelial (HK-2) cells. Our results demonstrated that BMS treatment markedly improved renal function, reduced tubular injury, and alleviated renal inflammation in mice. These protective effects were tightly associated with the inhibition of ferroptosis, as evidenced by reduced lipid peroxidation, decreased iron deposition, improved mitochondrial function, and the reversal of abnormal expression of key ferroptosis-related proteins, glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long chain family member 4 (ACSL4). Furthermore, in vitro experiments confirmed that BMS effectively mitigated RSL3-induced ferroptosis in HK-2 cells. To our knowledge, this study is the first to demonstrate that FABP4 exacerbates SA-AKI by promoting ferroptosis, suggesting that targeted inhibition of FABP4 may represent a promising novel therapeutic strategy for SA-AKI.