• Lysosomal damage in renal tubular epithelial cells is a key driver of diabetic kidney disease (DKD) pathogenesis, leading to autophagy impairment and oxidative stress imbalance.
• Melatonin (MLT) upregulates transcription factor EB (TFEB) to restore lysosomal biogenesis and function, thereby mitigating DKD-related kidney injury.
• The protective mechanism involves the miR-205-5p-LRP-1 pathway, linking MLT to improved autophagy and redox homeostasis in renal tubules.
• These findings suggest MLT as a potential therapeutic agent for DKD by targeting lysosomal integrity, offering a novel approach beyond current treatments.