Identification of GALNT14 as a Key Regulator of Ferroptosis in Cisplatin-Induced Acute Kidney Injury: A Potential Target for Kidney Injury Treatment

INTRODUCTION: Cisplatin-induced acute kidney injury (Cis-AKI) is a significant cause of renal damage, characterized by tubular injury, ferroptosis, and oxidative stress. While therapeutic options for Cis-AKI remain limited, identifying novel targets to prevent kidney injury is critical. This study focuses on GALNT14, a gene associated with ferroptosis, and its potential role in mitigating Cis-AKI. METHODS: The Limma package was used to analyze differentially expressed genes (DEGs) between the saline and cisplatin groups. The weighted correlation network analysis (WGCNA) was performed to discover the co-expressed modules and hub genes linked with Cis-AKI. The hub genes were then put into String database to create a network of protein-protein interactions. The FerrDb database was used to acquire genes related to ferroptosis, which were then screened for their association with CiS-AKI. The role of GALNT14 was examined in vitro using HK-2 renal tubular cells and in vivo in a Cis-AKI murine model. RESULTS: Totally, 1,201 DEGs in intravenous (iv) administration group were retrieved. The 806 genes were obtained from intersection WGCNA and DEGs. Ultimately, we identified 4 genes (ALOX5, CD44, GALNT14, and ASNS) that may play important roles in the regulation of ferroptosis in Cis-AKI. The mRNA expression level of GALNT14 exhibited the most notable difference between Cis-AKI and the control group. In vitro, GALNT14 overexpression in HK-2 cells reduced renal injury and ferroptosis markers, including KIM1, NGAL, and FSP1, while increasing GPX4 expression. Conversely, silencing GALNT14 exacerbated Cis-AKI-induced injury. In vivo, GALNT14 overexpression in Cis-AKI mice attenuated kidney injury, reduced ferroptosis markers, and reversed pathological alterations such as tubular dilatation and loss of brush border. CONCLUSION: GALNT14 inhibits Cis-AKI by regulating tubular ferroptosis, demonstrating its potential as a therapeutic target for kidney injury. Our findings suggest that GALNT14 could be an effective strategy for preventing Cis-AKI and improving renal function in kidney injury-related diseases.