C7ORF41 Alleviates Ferroptosis Via the Keap1/Nrf2/HO-1 Axis in Endotoxin-Associated Acute Kidney Injury

Endotoxin-associated acute kidney injury (EA-AKI) is a critical complication in intensive care units. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, has been implicated in EA-AKI; however, its regulatory mechanisms remain unclear. Prior research links C7ORF41 to anti-inflammatory effects and cellular stress regulation. This study aimed to investigate the role of C7ORF41 in EA-AKI and its connection with ferroptosis. We used C7ORF41 knockout (KO) mice and wild-type (WT) mice to evaluate the impact of C7ORF41 on renal function and ferroptosis in an LPS-induced AKI model. Human renal cortical proximal tubular epithelial (HK-2) cells were transfected with C7ORF41 shRNA or control vector to study the role of C7ORF41 in ferroptosis in vitro. We measured serum creatinine (sCr), blood urea nitrogen (BUN), reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) levels, as well as the expression of ferroptosis-related proteins. C7ORF41 expression was decreased in the kidneys of endotoxemic mice and in LPS-treated HK-2 cells. C7ORF41 deficiency significantly exacerbated LPS-induced lipid peroxidation, tissue damage, and renal dysfunction. In vitro, C7ORF41 knockdown increased ferroptotic cell death, lipid ROS, and decreased GPX4 expression. Mechanistically, C7ORF41 deficiency promotes ferroptosis in EA-AKI through the Keap1/Nrf2/HO-1 axis, highlighting its potential as a therapeutic target for EA-AKI treatment. This study provides new insights into the molecular mechanisms underlying ferroptosis in EA-AKI and offers a potential therapeutic strategy for this severe clinical condition.