RNA-Binding Protein Lgals3 , Ferroptosis, and Acute Kidney Injury.

Abstract

<i>LGALS3</i> was increased in the process of AKI. The inhibition of <i>LGALS3</i> alleviated kidney injury <i>in vivo</i> and <i>in vitro</i>. <i>LGALS3</i> contributed to kidney injury by binding to the 3′untranslated region of <i>Nr4a1</i> through AAUAAA, leading to the activation of ferroptosis. AKI is a syndrome characterized by a precipitous decline in kidney function, posing a significant threat to patient survival. The role of RNA-binding protein in AKI remains insufficiently understood, and we found an important RNA-binding protein, <i>LGALS3</i>, that may mediate the progress of AKI. <i>Lgals3</i>^−/− mice, <i>Nr4a1</i>^−/− mice, and cross-linking immunoprecipitation and high-throughput sequencing were performed to examine the role of <i>Lgals3</i> in AKI and the targeted binding proteins. <i>Lgals3</i> expression was notably elevated <i>in vivo</i> and <i>in vitro</i> AKI models. The inhibition of <i>Lgals3</i> mitigated kidney injury in both <i>in vivo</i> and <i>in vitro</i> AKI models. Conversely, kidney-specific overexpression of <i>Lgals3</i> exacerbated kidney damage. Mechanistically, <i>Lgals3</i> bound to the 3′-untranslated region of <i>Nr4a1</i> through AAUAAA, resulting in upregulation of <i>Nr4a1</i> and subsequent enhancement of <i>Bap1</i> transcription, facilitating ferroptosis in AKI. Moreover, knockout of <i>Nr4a1</i> or inhibition of the region of AAUAAA by antisense oligonucleotide conferred protection against <i>Lgals3</i>-induced ferroptosis in AKI models. <i>LGALS3</i> contributed to kidney injury by binding to the 3′untranslated region of <i>Nr4a1</i> through AAUAAA, leading to the activation of ferroptosis.