Targeting sirtuins in diabetic retinopathy: Differential roles in inflammation and mitochondrial dysfunction

Diabetic retinopathy (DR) is among the most prevalent microvascular complications of diabetes, with its onset and progression largely driven by chronic inflammation and mitochondrial dysfunction(definition). In recent years, the nicotinamide adenine dinucleotide+ dependent deacetylase family, sirtuins (SIRTs), has attracted growing attention for their integral roles in metabolic regulation, oxidative stress defense, inflammatory control, and cellular longevity. This review delineates the differential and stage-specific roles of SIRT isoforms in DR pathogenesis. SIRT1 attenuates inflammatory signaling by deacetylating key transcription factors, including nuclear factor-κB, and their target gene promoters, whereas the mitochondria-localized. SIRT3 directly deacetylates and activates antioxidant and metabolic enzymes to sustain reactive oxygen species balance and energy metabolism. Conversely, SIRT5 restores autophagic flux by desuccinylating optineurin at lysine-108, highlighting a novel link between post-translational modification and mitochondrial quality control. Accumulating preclinical evidence further indicates that various natural compounds and small-molecule activators, such as resveratrol, honokiol, and plant polyphenols, ameliorate DR-related pathology by upregulating SIRT signaling. By integrating current evidence, we highlight SIRTs as promising but complex therapeutic targets, underscoring the need for stage-specific intervention strategies and further research into less-explored isoforms to fully exploit their therapeutic potential.