STAT1/SLC31A1 signaling promotes diabetic retinopathy progression by mediating cuproptosis-induced M1 polarization in...

One of the main causes of vision impairment in diabetics is diabetic retinopathy (DR). However, the molecular mechanisms controlling its progression remains incompletely known. In this research, we identified the STAT1/SLC31A1 signaling pathway as a key regulator of cuproptosis-induced M1 polarization in microglial cells, thereby contributing to the pathogenesis of DR. STAT1 expression was markedly elevated under settings of high glucose (HG), both in in vitro experiments and in streptozotocin (STZ)-induced diabetic mouse models. Mechanistically, STAT1 transcriptionally upregulated the copper transporter SLC31A1, leading to copper accumulation and enhanced cuproptosis, as indicated by decreased levels of L-DLAT, FDX1, and NDUFS8. This cellular stress promoted M1 polarization and increased the expression of pro-inflammatory cytokines. Inhibition of either STAT1 or SLC31A1 significantly attenuated HG-induced cuproptosis and microglial activation. In vivo, STAT1 inhibition reduced retinal inflammation and structural damage, supporting its pathological role in DR progression. These findings confirm that the STAT1/SLC31A1/cuproptosis axis is a critical driver of microglial polarization and retinal injury and imply that SLC31A1 may act as DR's potential therapeutic target.