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Ferroptosis, characterized by lipid accumulation in intracellular compartments, is related to acute kidney injury (AKI), but the mechanism remains obscure. In our previous study, the protective effect of augmenter of liver regeneration (ALR) on AKI was not fully clarified. In this study, we established an AKI mouse model by knocking out proximal tubule‐specific ALR and an AKI cell model by inducing hypoxia, as well as enrolled AKI patients, to investigate the effects of ALR on ferroptosis and the progression of AKI. We found that ALR knockout aggravated ferroptosis and increased ROS accumulation and mitochondrial damage, whereas ALR overexpression attenuated ferroptosis through clearance of ROS and maintenance of mitochondrial morphology. Mechanistically, we demonstrated that ALR could directly bind to long‐chain‐fatty‐acid‐CoA ligase 4 (ACSL4) and further inhibit the expression of ACSL4 by interacting with certain regions. By resolution liquid chromatography coupled with triple quadruple mass spectrometry, we found that ALR could reduce the contents of polyunsaturated fatty acids, especially arachidonic acid. In addition, we showed that ALR binds to ACSL4 and attenuates oxylipin accumulation, exerting a protective effect against ferroptosis in AKI. Therefore, targeting renal ALR can attenuate ferroptosis and can offer a promising strategy for the treatment of AKI. [ABSTRACT FROM AUTHOR]

An early and accurate diagnosis of septic cardiomyopathy is vital for improving the overall prognosis of sepsis. In our research, we aimed to identify signature genes and their immune connections in septic cardiomyopathy. By analyzing the mouse myocardial transcriptome from sepsis induced by cecum ligation and puncture (CLP), we identified four distinct k-means clusters. Further analysis of human myocardial datasets using Weighted Gene Co-expression Network Analysis (WGCNA) revealed a strong correlation between the MEturquoise module and septic cardiomyopathy (cor = 0.79, p  < .001). Through the application of Cytoscape plug-in MCODE and comprehensive analysis, we pinpointed two signature genes, THBS1 and TIMP1. These genes demonstrated significant involvement in immune cell infiltration, as detected by CIBERSORT, and displayed promising prognostic potential as validated by external datasets. Our experimental validation confirmed the up-regulation of both THBS1 and TIMP1 in septic murine hearts, underscoring their positive association with septic cardiomyopathy.

Reactive oxidative species (ROS) production-driven ferroptosis plays a role in acute kidney injury (AKI). However, its exact molecular mechanism is poorly understood. Scavenger receptor CD36 has important roles in oxidizing lipids, lipid accumulation, metabolic syndrome, and insulin resistance in chronic kidney disease, but its roles remain unexplored in AKI. The present study investigated the role and mechanism of CD36 in regulating proximal tubular cell ferroptosis and AKI. The expression of CD36 was found to be significantly up-regulated in AKI renal tissues and correlated with renal function, which might serve as an independent biomarker for AKI patients. Moreover, in adult mice subjected to AKI, deletion of CD36 (CD36 -/- ) induced tubular cell ROS accumulation, ferroptosis activation, and renal injury. Mechanistically, combining LC-MS/MS, co-IP, and ubiquitination analyses revealed that CD36 could specifically bind to ferroptosis suppressor protein 1 (FSP1) and regulate its ubiquitination at sites K16 and K24, leading to FSP1 degradation and progression of ferroptosis in AKI. The present results emphasize a novel mechanism of CD36 in cisplatin-induced AKI. The discovery of the special CD36 roles in promoting ferroptosis and AKI development by regulating the ubiquitination of FSP1 in proximal tubular cells may be potential therapeutic targets for AKI. Moreover, CD36 may play a key role in the progression of AKI. Therefore, targeting CD36 may provide a promising treatment option for AKI., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)