Abstract <p>Photoreceptor death is a major and common pathological hallmark of many human retinal diseases, for which effective curative treatments are lacking. Colony-stimulating factor 1 receptor (CSF1R) has been implicated in microglia-associated inflammatory responses, with its overexpression reported in retinal disorders. Therefore, exploring the role of CSF1R signaling in photoreceptor death and viability is essential. GW2580 is a selective CSF1R inhibitor. In this study, we first evaluated the therapeutic efficacy of GW2580 in vivo using a zebrafish model of intense light-induced retinal injury. Next, we investigated the effects of GW2580 on microglial inflammation, neurotoxicity, and polarization phenotypes. Finally, using a co-culture model of microglial cells and photoreceptor cells, we investigated the protective role of GW2580 against oxidative stress-induced photoreceptor cell death. The results showed that intraocular administration of GW2580 markedly promoted photoreceptor regeneration following retinal injury. GW2580 treatment also reduced the expression of pro-inflammatory cytokines and reactive oxygen species levels, as well as promoted microglial transition from M1 to M2. In addition, GW2580 modulated autophagy- and apoptosis-related genes expression and restored photoreceptor-associated gene expression. Collectively, these findings suggest that CSF1R inhibition alleviates microglia-mediated inflammation and oxidative stress, modulates apoptosis and autophagy-related pathways, thereby reducing photoreceptor damage. These results highlight GW2580 as a promising therapeutic strategy for retinal diseases.</p>