BACKGROUND Diabetic retinopathy (DR) is one of the most common and serious complications of diabetes mellitus (DM). The autophagy-lysosome pathway (ALP) is one of the main intracellular self-digestive degradation systems. Lysosomal impairment and autophagic dysfunction are early events in the pathogenesis of DR, suggesting autophagy might be a novel therapeutic strategy for DR treatment. MATERIAL AND METHODS In our study, we screened a differentially expressed miRNA, miR-1273g-3p, in streptozotocin (STZ)-injected DR rat retinal pigment epithelial (RPE) cells. miR-1273g-3p inhibitor and mimic were employed to treat RPE cells to assess the role of miR-1273g-3p. QRT-PCR and Western blot analysis were performed to examine the function of miR-1273g-3p on ALP-related and DR-related proteins. RESULTS miR-1273g-3p was highly expressed in STZ-induced DM RPE cells. miR-1273g-3p mimic promoted the expression of DR-related MMP-2, MMP-9, and TNF-α proteins, and ALP-related LC3, cathepsin B, and cathepsin L factors, but miR-1273g-3p inhibitor suppressed the levels of these factors. CONCLUSIONS miR-1273g-3p is involved in the progression of DR by modulating the autophagy-lysosome pathway. These findings provided new evidence of the close relationship between DR and ALP, and reveal a new target for DR therapy.