Diosmetin alleviates retinal ischemia-reperfusion injury through SIRT1-mediated suppression of oxidative stress, inflammation, and PANoptosis.

Abstract

BACKGROUND: Retinal ischemia-reperfusion (RI/R) injury causes vision loss and lacks effective treatments. The role of diosmetin (DIO) in this condition, particularly through the SIRT1/Nrf2 pathway and its effect on PANoptosis, is unknown. METHODS: An in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model was developed using R28 retinal precursor cells, while an in vivo rat model of retinal ischemia/reperfusion (RI/R) was created through transient intraocular pressure elevation. DIO was administered in vitro, at the onset of reperfusion, and in vivo, via intraperitoneal injection. Cell viability, proliferation, oxidative stress markers, inflammatory cytokines, and PANoptosis-related protein expression were assessed. The role of SIRT1 was confirmed using siRNA knockdown in vitro and the pharmacological inhibitor EX527 in vivo. RESULTS: DIO treatment notably enhanced cell viability and proliferation in OGD/R-injured R28 cells, while also maintaining retinal structure and neuronal survival in RI/R-injured rats. DIO stimulated the SIRT1/Nrf2 pathway, evidenced by elevated levels of SIRT1, nuclear Nrf2, and HO-1 expression. This activation diminished oxidative stress, evidenced by lower ROS and MDA levels and higher SOD, CAT, and GSH levels, while also reducing inflammation, as indicated by decreased TNF-α, IL-1β, and IL-18. Consequently, DIO inhibited PANoptosis by downregulating key markers of apoptosis (cleaved caspase-3, BAX), pyroptosis (NLRP3, GSDMD), and necroptosis (p-RIPK3, p-MLKL). The beneficial effects of DIO, including neuroprotection, antioxidant activity, anti-inflammation, and anti-PANoptosis, were entirely nullified by SIRT1 knockdown or inhibition. CONCLUSION: DIO protects against retinal I/R injury by activating SIRT1/Nrf2 to inhibit oxidative stress, inflammation, and PANoptosis, highlighting its therapeutic potential.

Key Findings

• Diosmetin (DIO) treatment enhances cell viability and proliferation in retinal precursor cells subjected to oxygen-glucose deprivation/reperfusion injury.
• DIO activates the SIRT1/Nrf2 pathway, leading to increased expression of SIRT1, nuclear Nrf2, and HO-1, which reduces oxidative stress markers (ROS, MDA) and increases antioxidant enzymes (SOD, CAT, GSH).
• DIO suppresses inflammation by decreasing pro-inflammatory cytokines (TNF-α, IL-1β, IL-18) and inhibits PANoptosis by downregulating apoptosis, pyroptosis, and necroptosis markers; these effects are abolished by SIRT1 inhibition or knockdown.

Clinical Significance

Citation

Fu Peng, Wan Xiaobo, Zheng Chunronget al.. Diosmetin alleviates retinal ischemia-reperfusion injury through SIRT1-mediated suppression of oxidative stress, inflammation, and PANoptosis. Immunologic research. 2026-Aug-08.