YY1 lactylation exacerbates autoimmune uveitis by enhancing microglial functions via inflammatory genes. In experimental autoimmune uveitis (EAU) mice, increased YY1 lactylation in retinal microglia was observed, which promoted microglial activation, proliferation, and migration. Inhibition of lactylation suppressed these microglial functions and attenuated inflammation. Mechanistically, YY1 lactylation regulated the transcription of inflammatory genes (STAT3, CCL5, IRF1, IDO1, and SEMA4D) through p300, the writer of YY1 lactylation. Targeting the lactate/p300/YY1 lactylation/inflammatory genes axis may provide therapeutic benefits for autoimmune uveitis.YY1 lactylation exacerbates autoimmune uveitis by enhancing microglial functions via inflammatory genes. In experimental autoimmune uveitis (EAU) mice, increased YY1 lactylation in retinal microglia was observed, which promoted microglial activation, proliferation, and migration. Inhibition of lactylation suppressed these microglial functions and attenuated inflammation. Mechanistically, YY1 lactylation regulated the transcription of inflammatory genes (STAT3, CCL5, IRF1, IDO1, and SEMA4D) through p300, the writer of YY1 lactylation. Targeting the lactate/p300/YY1 lactylation/inflammatory genes axis may provide therapeutic benefits for autoimmune uveitis.