Strawberry anthocyanin pelargonidin-3-glucoside attenuated OA-induced neurotoxicity by activating UPR^mt

In this study, network pharmacology analysis revealed that strawberry anthocyanins mainly interfered with lipid metabolism and nerve-related signaling pathways. Pelargonidin-3-glucoside (Pg3G), one of the main anthocyanins in strawberry, was screened as the most effective anthocyanin for attenuating excess lipid accumulation. Moreover, Pg3G decreased lipid levels, relieved oxidative stress, and restored abnormal behavioral activities in Caenorhabditis elegans under oleic acid (OA) exposure. Meanwhile, Pg3G increased the expression of HSP-6 and HSP-60 proteins and activated the mitochondrial unfolded protein response (UPR^mt), while beneficial effects of Pg3G were impaired in the ubl-5 knockout strain, suggesting that ubl-5 may be a key target for improving OA-induced neurotoxicity. Expressions of neurotransmitter transmission-related genes showed great correlations with genes involved in lipid metabolism and UPR^mt, further explaining the underlying mechanism of Pg3G in neuroprotection. Our findings emphasize the key role of UPR^mt in alleviating OA-induced neurotoxicity of Pg3G, providing a theoretical basis for the research and development of strawberry anthocyanins as a dietary supplement for lipid reduction and treatment of neurodegenerative diseases.