{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:08:19Z","timestamp":1785424099738,"version":"3.56.0"},"reference-count":134,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jack Brown and Family Alzheimer\u2019s Disease Research Foundation"},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"crossref","award":["GR011587"],"award-info":[{"award-number":["GR011587"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]},{"award":["GR011587"],"award-info":[{"award-number":["GR011587"]}],"id":[{"id":"https:\/\/ror.org\/01h531d29","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent studies support the concept of a bidirectional lung\u2013brain axis. While neural, immune, and microbial pathways are increasingly recognized in lung-to-brain communication, the role of matrikines\u2014bioactive peptides generated by extracellular matrix (ECM) proteolysis during remodeling\u2014in this inter-organ communication remains underexplored. This review highlights matrikines originating from the lung, particularly the collagen-derived tripeptide Pro-Gly-Pro (PGP) and the elastin-derived hexapeptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG), as potential mediators linking pulmonary pathology with neurological outcomes. The lung is rich in ECM proteins, and inflammatory conditions such as chronic obstructive pulmonary disease (COPD) and emphysema trigger proteolytic activity by matrix metalloproteinases (MMPs) and neutrophil elastase, releasing matrikines into circulation. Under conditions of blood\u2013brain barrier (BBB) dysfunction, they may access the central nervous system (CNS), where they influence neurons, microglia, and astrocytes, modulating neuroinflammation, autophagy, and synaptic integrity. While PGP can exhibit context-dependent neuroprotective effects, its acetylated form and VGVAPG are associated with neurotoxicity, Tau hyperphosphorylation, and microglial activation. Additional matrikines, including Gly-His-Lys (GHK) and endorepellin, may further modulate CNS homeostasis. Collectively, these findings support lung-derived matrikines as circulating mediators of lung-to-brain signaling, providing a novel mechanistic framework linking chronic pulmonary inflammation to neuropathologies, such as stroke and neurodegenerative disorders, and highlighting potential targets for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/ijms27073339","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T07:25:12Z","timestamp":1775633112000},"page":"3339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Extracellular Matrix-Derived Matrikines: Circulating Peptides as Candidate Mediators of Lung-to-Brain Signaling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6587-6458","authenticated-orcid":false,"given":"Andis","family":"Klegeris","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC V1V 1V7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1152\/physrev.00018.2018","article-title":"The microbiota-gut-brain axis","volume":"99","author":"Cryan","year":"2019","journal-title":"Physiol. 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