Supplementary Material for: m6A eraser FTO promotes ATF3 expression impairing podocyte autophagy in diabetic nephropathy

Diabetic nephropathy (DN) is characterized by podocyte injury and proteinuria, in which impaired autophagy is a key pathological contributor. Although emerging evidence suggests an important role for m6A RNA modifications in autophagy regulation, their precise function in DN remains unclear. Here, we identify the m6A demethylase FTO as a critical driver of DN. FTO expression is significantly upregulated in podocytes from patients with DN and correlates with increased expression of ATF3, which acted as a transcriptional repressor inhibiting podocyte autophagic flux. Mechanistically, FTO overexpression decreases m6A modification on ATF3 mRNA, stabilizing its transcripts and thus suppressing the transcription of autophagy-related genes. Functionally, FTO overexpression disrupts autophagy in podocytes, whereas FTO knockdown rescues autophagy and preserves podocyte health under high glucose condition. In a mouse model of DN, podocyte-specific knockout of Fto prevents proteinuria, glomerulosclerosis, and podocyte injury, thereby ameliorating DN pathology. These findings reveal a novel FTO-ATF3 regulatory axis in diabetic kidney disease and position FTO gain-of-function as a pivotal factor in DN progression.