{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T14:14:06Z","timestamp":1778249646977,"version":"3.51.4"},"reference-count":42,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cell Biochemistry &amp;amp; Function"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Long dismissed as a passive marker of ventilatory failure, elevated carbon dioxide (PaCO\u2082\u2009&gt;\u200945\u2009mmHg) is now recognized as a potent signaling molecule that orchestrates complex cellular responses. This review synthesizes recent advances revealing how hypercapnia modulates fundamental processes, immune regulation, tissue repair, and metabolism, through direct molecular mechanisms. We detail how CO\u2082 triggers noncanonical NF\u2010\u03baB signaling, alters Wnt ligand secretion to impair alveolar regeneration, and exacerbates TLR4\u2010primed NLRP3 inflammasome activation; this pro\u2010inflammatory effect is most prominent in specific cell types like microglia and under conditions of sustained high CO\u2082 levels. Furthermore, hypercapnia drives profound metabolic reprogramming and induces lasting epigenetic changes, such as\n                    <jats:italic>TET1<\/jats:italic>\n                    \u2010downregulation\u2010mediated\n                    <jats:italic>CDH1<\/jats:italic>\n                    hypermethylation, which reinforces immunosuppression in chronic lung disease. Critically, we evaluate emerging tools like CarboSen probes that enable more precise separation of CO\u2082\u2010specific effects from associated acidosis in buffered experimental systems. Therapeutically, these insights argue for precision strategies: macrophage\u2010specific Akt1 inhibition to restore antiviral immunity, localized Wnt agonists to promote repair, or targeting the leptin\/STAT3\/SOCS3 axis to improve ventilatory drive. However, translation requires navigating significant species differences and unresolved questions regarding epigenetic reversibility. By framing hypercapnia not as a uniform stressor but as a complex modulator whose effects are dictated by concentration, duration, and the specific tissue type involved, this review charts a course toward targeting CO\u2082\u2010driven signaling for therapeutic benefit in conditions ranging from ARDS and COPD to obesity hypoventilation syndrome.\n                  <\/jats:p>","DOI":"10.1002\/cbf.70192","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T04:54:58Z","timestamp":1776228898000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypercapnia\u2010Regulated Molecular Pathways: Mechanistic Insights Into CO\u2082\u2010Driven Cellular Signaling and Therapeutic Implications"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0247-5451","authenticated-orcid":false,"given":"Mohammad\u2010Taher","family":"Moradi","sequence":"first","affiliation":[{"name":"Sleep Disorders Research Center, Health Policy and Promotion Institute Kermanshah University of Medical Sciences Kermanshah Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sepideh","family":"Nouraei","sequence":"additional","affiliation":[{"name":"Sleep Disorders Research Center, Health Policy and Promotion Institute Kermanshah University of Medical Sciences Kermanshah Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Habibolah","family":"Khazaie","sequence":"additional","affiliation":[{"name":"Sleep Disorders Research Center, Health Policy and Promotion Institute Kermanshah University of Medical Sciences Kermanshah Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir","family":"Sharafkhaneh","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine Baylor College of Medicine Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Babak","family":"Mokhlesi","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine Rush University Medical Center Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.735580"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.07-0027"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsmc.2024.02.009"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11113180"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2025.108252"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/17476348.2024.2331767"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9103207"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.347971"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsfs.2020.0039"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-54683-0"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.159331"},{"issue":"2","key":"e_1_2_14_13_1","first-page":"1814","article-title":"Ameliorating 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