{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T03:24:01Z","timestamp":1787887441289,"version":"build-2784847793"},"reference-count":76,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82560263"],"award-info":[{"award-number":["82560263"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82560263"],"award-info":[{"award-number":["82560263"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Yunnan Fundamental Research Projects","award":["202501AS070026"],"award-info":[{"award-number":["202501AS070026"]}]},{"name":"Key Research and Development Program of Yunnan Province","award":["202403AC100010"],"award-info":[{"award-number":["202403AC100010"]}]},{"name":"provincial-level project of the Undergraduate Innovation Training Program of Kunming Medical University","award":["PX-425764"],"award-info":[{"award-number":["PX-425764"]}]},{"award":["PX-425764"],"award-info":[{"award-number":["PX-425764"]}],"id":[{"id":"https:\/\/ror.org\/038c3w259","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>D-limonene (D-Lim) is a monocyclic monoterpene and the principal component of citrus essential oils; however, the potential mechanisms underlying its neuroprotective effects in traumatic brain injury (TBI) remain incompletely elucidated. By integrating network pharmacology, weighted gene co-expression network analysis (WGCNA), molecular docking, and experimental validation, this study systematically investigated the potential mechanisms through which D-Lim exerts neuroprotective activity. Database analyses and in vivo experiments showed that the anti-inflammatory and neuroprotective effects produced by D-Lim may be related to the p38 MAPK\/NF-\u03baB signaling axis and activation of the PI3K\/AKT signaling pathway. Molecular docking and RT-PCR experiments indicated interactions between D-Lim and potential target proteins, including Icam1, Kdr, and Dpp4. HE and Nissl staining demonstrated that D-Lim ameliorated TBI-induced neuronal injury. Moreover, D-Lim had no observable effects on major organs and showed no peripheral toxicity, suggesting its favorable applicability for TBI intervention. Following early intervention with D-Lim, the inflammatory response induced by TBI was attenuated, which may be associated with the activation or modulation of the p38 MAPK, PI3K\/AKT, and NF-\u03baB p65 signaling pathways. These results indicate a potential acute protective role for D-Lim under prophylactic or early-intervention conditions, provide insights into TBI intervention, and establish a theoretical basis for potential preventive strategies.<\/jats:p>","DOI":"10.3390\/ijms27146143","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:17:51Z","timestamp":1783606671000},"page":"6143","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated WGCNA and Network Pharmacology Explore the Potential Mechanisms of D-Limonene in Alleviating Traumatic Brain Injury"],"prefix":"10.3390","volume":"27","author":[{"given":"Hongyan","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0797-496X","authenticated-orcid":false,"given":"Hengxi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiying","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8571-8523","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.mcna.2019.11.001","article-title":"Traumatic Brain Injury: An Overview of Epidemiology, Pathophysiology, and Medical Management","volume":"104","author":"Capizzi","year":"2020","journal-title":"Med. 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