Oligo-peptide Pena-4 activates SIRT1 and exerts neuroprotective benefits against cerebral ischemia-reperfusion injury in mice

Purpose In ischemic stroke, the therapeutic options for mitigating ischemia/reperfusion (I/R) impairments in brain remain critically limited, underscoring an urgent need for novel neuroprotective agents. This study investigated the protective effects and underlying mechanisms of Pena-4, an oligopeptide originally identified from proteolytic digestion of Penaeus japonicus, in a model of transient middle cerebral artery occlusion/reperfusion (MCAO/R) . Methods Neurological function, infarct volume, and histopathological changes were evaluated after Pena-4 treatment. Network pharmacology and molecular docking were used to predict potential targets and pathways. Key proteins related to silent information regulator sirtuin 1 (SIRT1) signaling, oxidative stress, and pyroptosis were analyzed by western blotting, and malondialdehyde (MDA) levels were measured. Results Pena-4 notably improved neurological performance and decreased infarct volume. Histological analysis showed attenuated neuronal damage in the cortex and hippocampus. Network pharmacology approach identified 55 overlapping targets and highlighted silent information regulator sirtuin 1 (SIRT1) as a key hub target, which showed stable binding with Pena-4 in docking analysis. Pena-4 restored I/R-induced SIRT1 downregulation, increased SOD2 levels, reduced MDA content, and suppressed NLRP3-dependent pyroptosis, as evidenced by decreased NLRP3, cleaved caspase-1, and cleaved GSDMD. Conclusion Pena-4 thus confers neuroprotection against I/R impairments in brain through mechanisms that involve SIRT1 activation, enhanced antioxidant defense, and inhibition of NLRP3-dependent pyroptosis.