# NAT10 Promotes Tubular Epithelial Cell Senescence in Cisplatin-Induced Acute Kidney Injury by Regulating DDX17

## TL;DR

This study shows that NAT10 promotes kidney cell aging in cisplatin-induced kidney injury by regulating DDX17, suggesting a new treatment target.

## Contribution

The study identifies a novel NAT10/DDX17 signaling mechanism in cisplatin-induced renal tubular cell senescence.

## Key findings

- NAT10 inhibition reduces cisplatin-induced renal dysfunction and tubular injury.
- NAT10 interacts with DDX17 to regulate its expression and promote cell senescence.
- Targeting NAT10/DDX17 signaling may offer a therapeutic strategy for acute kidney injury.

## Abstract

Acute kidney injury (AKI) is a severe clinical syndrome with high morbidity and mortality, yet its pathogenesis remains incompletely understood, and effective therapeutic strategies are still lacking. In this study, we observed significant upregulation of N-acetyltransferase 10 (NAT10) in the tubular epithelial cells of Cisplatin-induced AKI. Lentivirus-mediated knockdown of NAT10 or treatment with NAT10 inhibitor Remodelin, ameliorated Cisplatin-induced renal dysfunction and tubular injury. Importantly, NAT10 inhibition markedly attenuated cellular senescence in Cisplatin-induced AKI, as evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity, downregulation of senescence markers (p53, p21 and γ-H2A.X) and decreased levels of senescence-associated secretory phenotype (SASP) factors (IL-1β, IL-6 and TNF-α). Mechanistically, co-immunoprecipitation assay suggested that NAT10 interacted with DDX17 to regulate its expression. Knockdown or inhibition of NAT10 reduced the protein expression of DDX17 in Cisplatin-injured kidneys. While silencing DDX17 could inhibit Cisplatin-induced senescence in HK-2 cells. Furthermore, we demonstrated that the effects of NAT10 on Cisplatin-induced tubular injury and senescence was dependent on DDX17. Our study revealed a novel mechanism by which NAT10 promoted Cisplatin-induced renal tubular cell senescence via DDX17 upregulation, suggesting that targeting the NAT10/DDX17 signaling axis may offer a potential therapeutic strategy for AKI.