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In this study, the aqueous extract of H. erectus was subjected to in vitro simulated gastrointestinal digestion and ultrafiltration to separate three molecular weight fractions (&lt;10 kDa, 10\u201330 kDa, &gt;30 kDa). Their chemical profiles were characterized, and osteogenic activities were systematically evaluated using cell assays, a juvenile rat model, and integrated transcriptomics and data-independent acquisition (DIA) proteomics. Results revealed that chemical profiling showed the &gt;30 kDa fraction was mainly composed of hemocyanin subunits, and the 10\u201330 kDa fraction was enriched in growth-related amino acids and steroid derivatives; functionally, the 10\u201330 kDa fraction promoted preosteoblast proliferation and early differentiation via enhanced alkaline phosphatase (ALP) activity, while the &gt;30 kDa fraction dominated late osteoblast maturation and mineralization. Both fractions significantly increased rat body and bone length by expanding growth plate proliferative zones and elevating serum insulin-like growth factor-1 (IGF-1)\/bone morphogenetic protein-2 (BMP-2) levels. Transcriptomic and proteomic analyses identified vascular endothelial growth factor (VEGF), Wingless-related integration site (Wnt), phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt), and extracellular matrix (ECM)\u2013receptor interaction as potential core regulatory pathways. Integrated multi-omics analysis further confirmed Frizzled-related protein B (Frzb) and AKT1 substrate 1 (Akt1s1) as candidate key regulatory targets enriched in the Wnt and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways. These findings elucidate the multi-fraction, multi-pathway mechanism of H. erectus in promoting skeletal development, providing scientific evidence for its traditional use and a theoretical basis for growth-promoting functional food development.<\/jats:p>","DOI":"10.3390\/cimb48070678","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:50:37Z","timestamp":1782867037000},"page":"678","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the Skeletal Growth-Promoting Mechanism of the Seahorse Hippocampus erectus: From Active Fraction Screening to Signaling Pathway Regulation"],"prefix":"10.3390","volume":"48","author":[{"given":"Lianghua","family":"Huang","sequence":"first","affiliation":[{"name":"Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"Guangxi Key Laboratory of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"University Engineering Research Center of High-Efficient Utilization of Marine Traditional Chinese Medicine Resources, Nanning 530200, China"},{"name":"Engineering Research Center of Innovative Drug of Traditional Chinese and Zhuang Yao Medicine, Ministry of Education, Guangxi University of Chinese Medicine, Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoji","family":"Pan","sequence":"additional","affiliation":[{"name":"Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"Guangxi Key Laboratory of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"University Engineering Research Center of High-Efficient Utilization of Marine Traditional Chinese Medicine Resources, Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Bai","sequence":"additional","affiliation":[{"name":"Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"Guangxi Key Laboratory of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"University Engineering Research Center of High-Efficient Utilization of Marine Traditional Chinese Medicine Resources, Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyan","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"Guangxi Key Laboratory of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"University Engineering Research Center of High-Efficient Utilization of Marine Traditional Chinese Medicine Resources, Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xiao","sequence":"additional","affiliation":[{"name":"Guangxi Engineering Research Center for High-Value Utilization of Guangxi-Produced Authentic Medicinal Herbs, Nanning 530200, China"},{"name":"Characteristic Chinese Traditional & Ethnic Medicine Engineering Research Center for Guangxi Universities, Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7524-8049","authenticated-orcid":false,"given":"Chenghai","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"Guangxi Key Laboratory of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China"},{"name":"University Engineering Research Center of High-Efficient Utilization of Marine Traditional Chinese Medicine Resources, Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","first-page":"4089","article-title":"Research Progress on Chemical Constituents and Pharmacological Activities of Hippocampus","volume":"48","author":"Chen","year":"2017","journal-title":"Chin. 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