{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T06:27:18Z","timestamp":1787120838035,"version":"build-2736575974"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Insomnia is increasingly recognized as a systemic disorder involving persistent hyperarousal, neuroendocrine dysregulation, immune activation, and impaired stress adaptation. However, circulating biomarkers reflecting these interconnected biological processes have not been comprehensively synthesized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a systematic review and meta-analysis of observational studies comparing circulating biomarkers between adults with insomnia and healthy controls. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using random- or fixed-effects models as appropriate. Subgroup analyses, sensitivity analyses, and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments were performed to evaluate the robustness and certainty of the evidence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Thirty-two studies involving 4578 individuals with insomnia and 28382 healthy controls were included. Cortisol levels were significantly elevated (SMD = 3.65, 95% CI: 2.35 to 4.95). Inflammatory biomarkers, including interleukin-6 (IL-6), tumor necrosis factor-\u03b1 (TNF-\u03b1), C-reactive protein (CRP), interleukin-1\u03b2 (IL-1\u03b2), interleukin-2 (IL-2), and interferon-\u03b3 (IFN-\u03b3), were significantly increased, whereas interleukin-4 (IL-4) and interleukin-10 (IL-10) showed no significant differences. Neuropeptide Y (NPY) was significantly reduced (SMD = \u22120.85, 95% CI: \u22121.27 to \u22120.43), while corticotropin-releasing hormone (CRH) and brain-derived neurotrophic factor (BDNF) showed no significant pooled differences. TNF-\u03b1, IL-1\u03b2, IL-6, CRP, and NPY showed generally consistent results in sensitivity analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Insomnia is associated with alterations in circulating biomarkers reflecting hypothalamic-pituitary-adrenal (HPA) axis activity, low-grade systemic inflammation, and potential reductions in stress-buffering capacity. This multidomain biomarker pattern provides insights into the biological basis of insomnia and highlights potential candidate biomarkers for future biological stratification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>\n                      , identifier CRD420261396725.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1889366","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:45:02Z","timestamp":1787118302000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomarker evidence for the pathophysiological mechanisms of insomnia: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Ying","family":"Wang","sequence":"first","affiliation":[{"name":"School of Acupuncture-Moxibustion and Tuina, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Fu","family":"Ji","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Acupuncture-Moxibustion and Tuina, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Heng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Acupuncture-Moxibustion and Tuina, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Shu","family":"Ma","sequence":"additional","affiliation":[{"name":"Innovation and Practice Center, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Liang","family":"Diao","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Yi","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"B1","volume-title":"Diagnostic and Statistical Manual of Mental Disorders: DSM-5-TR. 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