FTO Modulates m⁶A RNA Methylation of STC1 to Regulate Inflammation and Oxidative Stress in Diabetic Nephropathy

Diabetic nephropathy (DN) is a major cause of chronic kidney disease, driven by hyperglycemia-induced kidney damage. Recently research has highlighted the role of N6-methyladenosine (m⁶A) RNA methylation in the progression of DN. The role of the fat mass and obesity-associated protein (FTO), an essential m⁶A demethylase, in DN remains uncertain despite its association with various diseases. Datasets (GSE96804 and GSE30528) were used to identify differentially expressed genes in DN. Diabetic cell models were established by culturing human renal glomerular endothelial cells (HRGECs) and mesangial cells (HRMCs) in high glucose conditions. FTO expression was manipulated through overexpression and knockdown, and its effects on cell viability, apoptosis, ROS production, inflammatory factor secretion, and m⁶A modifications were assessed. In vivo, db/db mice were used to evaluate the therapeutic potential of FTO and stanniocalcin-1 (STC1) gene modulation. FTO was significantly downregulated in DN models, and overexpression of FTO in HRGECs under high glucose conditions alleviated oxidative stress, reduced inflammation, and improved cell viability. LSP1P5 and STC1 were identified as potential downstream targets of FTO, with m⁶A methylation levels of STC1 significantly altered by FTO modulation. In vivo, FTO overexpression improved kidney function and mitigated inflammation and oxidative stress, whereas STC1 exacerbated kidney injury, indicating a complex interplay between FTO and STC1 in DN progression. This study demonstrates that FTO modulates m⁶A RNA methylation of STC1 to regulate inflammation and oxidative stress in DN. Targeting the FTO/STC1 axis may offer a novel therapeutic strategy for managing DN and preventing kidney damage.