{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:09:27Z","timestamp":1778479767149,"version":"3.51.4"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Fracture healing is a complex regenerative process requiring coordinated interactions among vascular, skeletal, and neural systems. Angiogenesis is a critical rate-limiting step that regulates oxygen delivery, inflammatory resolution, and osteogenic cell recruitment within the fracture microenvironment. Huoxue Jiegu Compound Capsule (HXJGCC), a traditional Chinese medicine formulation, has demonstrated clinical efficacy in fracture management; however, its molecular mechanisms underlying fracture repair remain insufficiently elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An integrative strategy combining network pharmacology, molecular docking, 100-ns molecular dynamics simulations, and\n                      <jats:italic>in vivo<\/jats:italic>\n                      experimental validation was employed to investigate the mechanisms of HXJGCC in tibial fracture healing. Candidate bioactive compounds and potential therapeutic targets were identified, followed by protein\u2013protein interaction (PPI) network construction and functional enrichment analyses. A rabbit tibial segmental defect model was established to validate angiogenesis-related effects using histological analysis and qRT-PCR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 209 candidate active compounds and 185 overlapping targets were identified. Network analysis revealed key hub targets, including AKT1, STAT3, IL6, BCL2, EGFR, and JUN, which were significantly enriched in angiogenesis-related signaling pathways, particularly HIF-1, PI3K\u2013Akt, Relaxin, TNF, and FoxO pathways. Molecular docking and molecular dynamics simulations demonstrated stable interactions between core compounds and target proteins, supporting a multi-component and multi-target mechanism. In vivo experiments showed that HXJGCC significantly increased vascular density and improved vascular architecture in the fracture region. qRT-PCR analysis further confirmed significant upregulation of angiogenesis-associated genes (AKT1, STAT3, IL6, and EGFR), indicating activation of pro-angiogenic regulatory networks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HXJGCC accelerates tibial fracture healing primarily by enhancing angiogenesis and improving the local microvascular microenvironment. Mechanistically, activation of HIF-1\/PI3K\u2013Akt-related signaling pathways may coordinate inflammatory responses, vascular remodeling, and downstream osteogenic processes. These findings support the establishment of an angiogenesis-driven repair framework, potentially integrating neuro\u2013vascular\u2013bone interactions, and provide mechanistic insights into the multi-target therapeutic effects of HXJGCC, highlighting angiogenesis-centered regulation as a promising strategy for promoting bone regeneration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1810673","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T05:29:55Z","timestamp":1778477395000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Huoxue Jiegu compound capsule accelerates tibial fracture healing via angiogenesis-driven repair mechanisms"],"prefix":"10.3389","volume":"13","author":[{"given":"Weisong","family":"Lu","sequence":"first","affiliation":[{"name":"Guizhou University of Traditional Chinese Medicine","place":["Guiyang, Guizhou, China"]},{"name":"Department of Orthopedics and Traumatology I, Luzhou Hospital of Traditional Chinese Medicine","place":["Luzhou, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Traumatology I, Suining Hospital of Traditional Chinese Medicine","place":["Suining, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Guizhou University of Traditional Chinese Medicine","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shixiang","family":"Tan","sequence":"additional","affiliation":[{"name":"Guizhou University of Traditional Chinese Medicine","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingjie","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Guizhou Provincial Third People's Hospital","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yangzhan","family":"Sun","sequence":"additional","affiliation":[{"name":"Guizhou University of Traditional Chinese Medicine","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengze","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Traumatology I, Luzhou Hospital of Traditional Chinese Medicine","place":["Luzhou, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hegui","family":"Xu","sequence":"additional","affiliation":[{"name":"Guizhou University of Traditional Chinese Medicine","place":["Guiyang, Guizhou, 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