Loss of nephric augmenter of liver regeneration facilitates acute kidney injury via ACSL4‐mediated ferroptosis

Abstract

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.

Ferroptosis: a novel mechanism of cell death in ophthalmic conditions

“…( 134 ) proposed that ferroptosis and programmed necrosis are complementary mechanisms of cell death. Within this framework, ACSL4, a key enzyme in lipid metabolism, was utilized as an indicator of ferroptosis, while mixed lineage kinase-like protein (MLKL), a protein involved in the execution of necrosis, served as a marker for programmed necrosis ( 135 , 136 ). These findings indicated that a deficiency in ACSL4 resulted in the upregulation of MLKL, which sensitized cells to ferroptosis ( 137 ).…”