Key Points

LGALS3 was increased in the process of AKI.The inhibition of LGALS3 alleviated kidney injury in vivo and in vitro.LGALS3 contributed to kidney injury by binding to the 3′untranslated region of Nr4a1 through AAUAAA, leading to the activation of ferroptosis.

Background

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, LGALS3, that may mediate the progress of AKI.

Methods

Lgals3−/− mice, Nr4a1−/− mice, and cross-linking immunoprecipitation and high-throughput sequencing were performed to examine the role of Lgals3 in AKI and the targeted binding proteins.

Results

Lgals3 expression was notably elevated in vivo and in vitro AKI models. The inhibition of Lgals3 mitigated kidney injury in both in vivo and in vitro AKI models. Conversely, kidney-specific overexpression of Lgals3 exacerbated kidney damage. Mechanistically, Lgals3 bound to the 3′-untranslated region of Nr4a1 through AAUAAA, resulting in upregulation of Nr4a1 and subsequent enhancement of Bap1 transcription, facilitating ferroptosis in AKI. Moreover, knockout of Nr4a1 or inhibition of the region of AAUAAA by antisense oligonucleotide conferred protection against Lgals3-induced ferroptosis in AKI models.

Conclusions

LGALS3 contributed to kidney injury by binding to the 3′untranslated region of Nr4a1 through AAUAAA, leading to the activation of ferroptosis.