GATA1 Transcriptionally Upregulates LMCD1, Promoting Ferroptosis in Sepsis-Associated Acute Kidney Injury Through the Hippo/YAP Pathway.

Abstract

Sepsis-associated acute kidney injury (SA-AKI) is associated with morbidity and mortality. Ferroptosis is associated with the pathophysiology of SA-AKI. Here, we investigated the role of LIM and cysteine-rich domain 1 (LMCD1) in the regulation of ferroptosis during SA-AKI progression. SA-AKI models were established by CLP and LPS treatments. Hematoxylin and eosin (HE) and (PAS) staining were conducted to examine renal pathological changes. ELISA was used to measure serum creatinine and BUN levels. Lipid ROS levels in cells were examined using flow cytometry. MDA, GSH, SOD, and Fe²⁺ levels in the cells were measured using appropriate kits. Molecular interactions were analyzed using ChIP, a dual-luciferase reporter gene, and Co-IP assays. GATA1 knockdown inhibits LPS-induced cell injury, oxidative stress, and ferroptosis in HK-2 cells by transcriptionally inhibiting LMCD1 expression. Moreover, LMCD1 activates the Hippo/YAP pathway by promoting CUL3-mediated Nrf2 ubiquitination degradation. LMCD1 knockdown alleviates CLP-induced AKI in mice by inhibiting ferroptosis. Taken together, LMCD1 transcriptionally activated by GATA1 promotes ferroptosis during SA-AKI progression by activating the Hippo/YAP pathway and facilitating CUL3-mediated Nrf2 ubiquitination degradation.