Objective To explore the molecular mechanism of histone acetyltransferase （p300） mediated peroxisome proliferator activated receptor-γ（PPAR-γ） influencing diabetes retinopathy through lipid peroxidation. Methods Diabetes models were established in 65 SD rats by intraperitoneal injection of streptozotocin， and the remaining 10 SD rats were simultaneously intraperitoneally injected with an equal amount of sterile physiological saline and recorded as the normal group. The successfully modeled rats were randomly divided into six groups： p300 upregulated group， p300 downregulated group， PPAR-γ upregulated group， PPAR-γ downregulated group， empty control group， and model group. Except for the normal group and the model group （which were simultaneously injected with an equal amount of sterile physiological saline through vitreous injection）， each group was injected with pcDNA-p300， si-p300， pcDNA PPAR-γ， si-PPAR-γ， and pcDNA adenovirus solution through vitreous injection. Five rats were selected from each group， and Evans blue method was used to detect the degree of damage to the left eye blood retinal barrier. The fully automated biochemical analyzer detects lipids in each group， including triglycerides （TG）， cholesterol （TC）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， as well as peroxidation reaction indicators such as superoxide dismutase （SOD） activity， malondialdehyde （MDA） content， and reactive oxygen species （ROS） levels. Five rats from each group were selected to take retinal tissue from their right eyes for hematoxylin eosin （HE） staining to observe pathological changes. After the remaining rats in each group were euthanized by decapitation， real time quantitative polymerase chain reaction （RT-qPCR） was used to detect the expressions of p300， PPAR-γ， protein kinase C β （PKC β）， and adaptor protein p66Shc （P66Shc） messenger RNA （mRNA） in the left eye retinal tissues， and Western blot was used to detect the expression of the aforementioned proteins and the phosphorylation level of P66Shc in the retinal tissues of the right eye. Results Compared with the normal group， the Evans blue concentrations， albumin penetrations， serum TG， TC， LDL-C， MDA contents， and ROS levels increased in all other groups， while HDL-C， SOD activity， p300， PPAR-γ， PKC β， P66Shc expressions， and P66Shc phosphorylation levels decreased （P < 0.05）. Compared with the model group， the p300 downregulated group showed a decrease in p300 expression （P < 0.05）， the Evans blue concentration， albumin permeability， serum TG， TC， LDL-C， MDA contents， and ROS levels were all increased in the p300 downregulated group and PPAR-γ downregulated group， while HDL-C and SOD activity， PPAR-γ， PKC β， P66Shc expression， and P66Shc phosphorylation levels were all decreased （P < 0.05）. The p300 upregulated group showed an increase in p300 expression （P < 0.05）， and the Evans blue concentration， albumin permeability， serum TG， TC， LDL-C， MDA contents， and ROS levels all decreased in the p300 upregulated group and PPAR-γ upregulated group， while HDL-C and SOD activity， PPAR-γ， PKC β， P66Shc expressions， and P66Shc phosphorylation levels all increased （P < 0.05）. There were no statistically significant differences in blood retinal barrier damage， lipid and peroxidation indicators， PPAR-γ， PKC β， P66Shc expression， and P66Shc phosphorylation between the p300 downregulated group and PPAR-γ downregulated group， p300 upregulated group and PPAR-γ upregulated group， unloaded control group and model group （P > 0.05）. Normal group rats showed no pathological changes in retinal tissues， while significant pathological changes were observed in the model group and empty control group. Severe pathological changes were observed in the p300 downregulated group and PPAR-γ downregulated group， while slight pathological changes were observed in the p300 upregulated group and PPAR-γ upregulated group. Conclusion Up-regulation of p300 can positively mediate PPAR-γ to control lipid peroxidation and alleviate diabetes retinopathy， while down-regulation of p300 can promote diabetes retinopathy by inhibiting PPAR-γ to activate lipid peroxidation.