Immunologic research · 2026
Diosmetin alleviates retinal ischemia-reperfusion injury through SIRT1-mediated suppression of oxidative stress, inflammation, and PANoptosis.
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Fu Peng, Wan Xiaobo, Zheng Chunrong, Wu Xiaonian, Xu Ke, Lin Qiuyu, Huang Minli
Аннотация
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.
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.