Andrographolide attenuates sepsis-induced acute kidney injury by inhibiting ferroptosis through the Nrf2/FSP1 pathway

experiments. Firstly, in septic rats and HK-2 cells, AG effectively decreased the levels of kidney injury indicators, including blood creatinine, urea nitrogen, and markers of kidney injury such as neutrophil gelatinase-associated lipid transport protein and kidney injury molecule-1 (KIM-1). In addition, AG prevented ferroptotosis, by avoiding the accumulation of iron and lipid peroxidation, and an increase in SLC7A11 and GPX4 in AG-treated HK-2 cells. Furthermore, AG attenuated mitochondrial damage, including mitochondrial swelling, outer membrane rupture, and a reduction in mitochondrial cristae in LPS-treated HK-2 cells. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, significantly inhibited LPS-induced ferroptosis in HK-2 cells. Importantly, our results confirm that Nrf2/FSP1 is an important pathway for ferroptosis resistance. Nrf2 siRNA hindered the effect of AG in attenuating acute kidney injury and inhibiting ferroptosis. These findings demonstrate that Nrf2/FSP1-mediated HK-2 ferroptosis is associated with AG, alleviates septic acute kidney injury, and indicates a novel avenue for therapeutic interventions in the treatment of acute kidney injury in sepsis.