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Despite the absence of thorough research, deer hide gelatin (DHG), a traditional Chinese medicine high in collagen, has shown promise in the prevention and treatment of skeletal and hematological disorders. This study aimed to evaluate the protective effects of DHG on chemotherapy-induced osteoporosis (OP) in rat bone tissue, as well as the material basis and mechanisms of its anti-OP activity. The results showed that DHG reversed the decrease in bone mineral density induced by chemotherapy, improved bone biomechanical properties, and ameliorated bone microstructure. DHG promoted the expression of the osteoblast-related indicators BALP and P1NP while suppressing the expression of the osteoclast-related marker TRACP-5b. Protein mass spectrometry screening was used to find putative anti-OP bioactive peptides. According to network pharmacology predictions, the PI3K signaling pathway may be the mechanism by which the active peptides in DHG produce their anti-OP actions. Additionally, immunofluorescence investigation demonstrated that DHG inhibited MMP9 expression while increasing RUNX2 expression. <jats:italic>In vitro<\/jats:italic> experiments also confirmed that DHG active peptides promoted bone formation by activating the PI3K\/AKT\/ERK signaling pathway, upregulating RUNX2 protein expression, and promoting osteoblast differentiation and mineralization. In conclusion, DHG has protective benefits against OP caused by chemotherapy. This also raises the possibility that DHG could be useful in the broader management of chemotherapy side effects (e.g., potentially related to cardio-oncology, considering the pathway\u2019s important role in organs like the heart), warranting further investigation.<\/jats:p>","DOI":"10.3389\/fphar.2025.1631924","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T05:35:04Z","timestamp":1759815304000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Bone-protective effects of deer-hide gelatin in cyclophosphamide-induced osteoporosis rats"],"prefix":"10.3389","volume":"16","author":[{"given":"Hongyun","family":"Mao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyue","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaoqin","family":"Mo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haili","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunfeng","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongqing","family":"Hua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"B2","doi-asserted-by":"publisher","first-page":"398","DOI":"10.22037\/ijpr.2020.112587.13843","article-title":"STAT3-mediated apoptotic-enhancing function of sclareol against breast cancer cells and cell sensitization to cyclophosphamide","volume":"19","author":"Afshari","year":"2020","journal-title":"Iran. 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