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This study investigated the osteoprotective effects of low, medium, and high doses of oyster peptide (OP) in dexamethasone (DEX)-induced osteoporotic rats. Pathological analysis showed that OP treatment effectively mitigated bone loss and repaired bone microarchitecture deterioration caused by DEX administration. In the OP groups, levels of the osteogenic markers osteocalcin (OCN) and osteoprotegerin (OPG) were significantly higher than in the DEX group. Moreover, levels of the osteoclastic markers RANKL, Cathepsin K (Cath-K), MMP-9, C-terminal telopeptide of type I collagen (CTX-1), and Deoxypyridine (DPD) were significantly lower. Bone proteomic analysis of the DEX and OP groups revealed that differentially expressed proteins were significantly enriched in pathways related to extracellular matrix and structural reorganization, ECM\u2013receptor interaction, and PI3K-Akt signaling. Furthermore, virtual screening simulations indicated that peptides with lengths ranging from 11 to 20 amino acid residues were involved in modulating the activity of key receptors in these pathways, including Integrins \u03b15\u03b21, Integrins \u03b1v\u03b23, and EGFR. Collectively, these results demonstrate the significant potential of OP as a novel therapeutic agent for osteoporosis.<\/jats:p>","DOI":"10.3390\/md23090356","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T08:55:02Z","timestamp":1757580902000},"page":"356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Improvement Effect and Regulation Mechanism of Oyster Peptide on Dexamethasone-Induced Osteoporotic Rats"],"prefix":"10.3390","volume":"23","author":[{"given":"Wei","family":"Yang","sequence":"first","affiliation":[{"name":"College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"National Research and Development Branch Center for Shellfish Processing (Zhanjiang), Zhanjiang 524088, China"},{"name":"Guangdong Provincial Key Laboratory of Aquatic Products Processing and Safety, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Province Engineering Laboratory for Marine Biological Products, Zhanjiang 524088, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"National Research and Development Branch Center for Shellfish Processing (Zhanjiang), Zhanjiang 524088, China"},{"name":"Guangdong Provincial Key Laboratory of Aquatic Products Processing and Safety, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Province Engineering Laboratory for Marine Biological Products, Zhanjiang 524088, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8415-8902","authenticated-orcid":false,"given":"Xiaoming","family":"Qin","sequence":"additional","affiliation":[{"name":"College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"National Research and Development Branch Center for Shellfish Processing (Zhanjiang), Zhanjiang 524088, China"},{"name":"Guangdong Provincial Key Laboratory of Aquatic Products Processing and Safety, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Province Engineering Laboratory for Marine Biological Products, Zhanjiang 524088, China"},{"name":"Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China"},{"name":"Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhong","family":"Cao","sequence":"additional","affiliation":[{"name":"College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"National Research and Development Branch Center for Shellfish Processing (Zhanjiang), Zhanjiang 524088, China"},{"name":"Guangdong Provincial Key Laboratory of Aquatic Products Processing and Safety, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Province Engineering Laboratory for Marine Biological Products, Zhanjiang 524088, China"},{"name":"Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9823-2584","authenticated-orcid":false,"given":"Haisheng","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"National Research and Development Branch Center for Shellfish Processing (Zhanjiang), Zhanjiang 524088, China"},{"name":"Guangdong Provincial Key Laboratory of Aquatic Products Processing and Safety, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Province Engineering Laboratory for Marine Biological Products, Zhanjiang 524088, China"},{"name":"Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1186\/s13018-021-02772-0","article-title":"The global prevalence of osteoporosis in the world: A comprehensive systematic review and meta-analysis","volume":"16","author":"Salari","year":"2021","journal-title":"J. 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