With the rising prevalence of diabetes and increasing life expectancy, diabetic nephropathy (DN) has become a leading cause of morbidity and mortality among diabetic patients (Grek and Arasi, 2016). However, treatment options for DN remain limited, with current therapies such as angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and sodium-glucose cotransporter-2 inhibitors offering modest efficacy (Ricciardi and Gnudi, 2021). DN is characterized by a complex pathogenesis, including glomerular basement membrane thickening, extracellular matrix accumulation in the glomerular mesangial area, and glomerulosclerosis, with or without tubulointerstitial fibrosis, ultimately leading to chronic renal failure (Qi et al., 2017; Samsu, 2021). Identifying susceptibility factors for DN is crucial for timely implementation of targeted prevention and intervention strategies.

Ferroptosis is a novel form of cell death induced by iron-dependent oxidative damage, resulting in the accumulation of reactive oxygen species (ROS) in membrane lipids. This mechanism differs significantly from other forms of cell death, such as apoptosis, necrosis, and autophagy (Mou et al., 2019; Xu et al., 2019). Ferroptosis is primarily characterized by the production of lipid ROS, whose clearance is largely dependent on glutathione peroxidase 4. Imbalances in lipid ROS production and clearance contribute to the onset of ferroptosis (Shen et al., 2018). The process has been implicated in various diseases and has emerged as a potential therapeutic target. Ferroptosis plays a role in cancer, acute kidney injury (AKI), neurodegenerative diseases, and ischemia/reperfusion injury (Xie et al., 2016). Recent studies suggest that ferroptosis of proximal tubular epithelial cells is involved in the onset and progression of DN (Kim et al., 2021a; Wang et al., 2020), highlighting the potential of ferroptosis-related biomarkers in diabetic conditions.

Several mechanisms have been identified as crucial in the progression of DN, with ferroptosis being a key contributor (Wang et al., 2024b). Given the involvement of multiple ferroptosis-related molecules, exploring key ferroptosis-related genes (FRGs) using bioinformatics approaches is essential. In this study, high-throughput data related to DN were collected and analyzed. The aim was to identify potential FRGs as diagnostic markers for DN, which could enhance the diagnosis and treatment of the disease. Furthermore, the relationship between differentially expressed FRGs (DE-FRGs) and disease-related pharmacological agents was investigated. To comprehensively validate the pathogenic role of candidate genes in DN, cross-species studies were conducted using both animal models and human clinical samples.