| Summary: | <i>Hippophae rhamnoides</i> L. has been widely used in research and application for almost two decades. While significant progress was achieved in the examination of its fruits and seeds, the exploration and utilization of its by-products have received relatively less attention. This study aims to address this research gap by investigating the effects and underlying mechanisms of sea buckthorn seed residues both in vitro and in vivo. The primary objective of this study is to assess the potential of the hydroalcoholic extract from sea buckthorn seed residues (HYD-SBSR) to prevent cell apoptosis and mitigate oxidative stress damage. To achieve this, an H<sub>2</sub>O<sub>2</sub>-induced B16F10 cell model and a D-galactose-induced mouse model were used. The H<sub>2</sub>O<sub>2</sub>-induced oxidative stress model using B16F10 cells was utilized to evaluate the cellular protective and reparative effects of HYD-SBSR. The results demonstrated the cytoprotective effects of HYD-SBSR, as evidenced by reduced apoptosis rates and enhanced resistance to oxidative stress alongside moderate cell repair properties. Furthermore, this study investigated the impact of HYD-SBSR on antioxidant enzymes and peroxides in mice to elucidate its reparative potential in vivo. The findings revealed that HYD-SBSR exhibited remarkable antioxidant performance, particularly at low concentrations, significantly enhancing antioxidant capacity under oxidative stress conditions. To delve into the mechanisms underlying HYD-SBSR, a comprehensive proteomics analysis was conducted to identify differentially expressed proteins (DEPs). Additionally, a Gene Ontology (GO) analysis and an Encyclopedia of Genes and Genomes (KEGG) pathway cluster analysis were performed to elucidate the functional roles of these DEPs. The outcomes highlighted crucial mechanistic pathways associated with HYD-SBSR, including the PPAR signaling pathway, fat digestion and absorption, glycerophospholipid metabolism, and cholesterol metabolism. The research findings indicated that HYD-SBSR, as a health food supplement, exhibits favorable effects by promoting healthy lipid metabolism, contributing to the sustainable and environmentally friendly production of sea buckthorn and paving the way for future investigations and applications in the field of nutraceutical and pharmaceutical research.
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