{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:40:14Z","timestamp":1780447214522,"version":"3.54.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"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. Cell. Neurosci."],"abstract":"<jats:p>The blood\u2013brain barrier (BBB) is a critical interface whose failure is a convergent pathological feature of traumatic, ischemic, and neurodegenerative neurological diseases. Current paradigms often overlook the synergistic interplay between mechanical forces and biochemical cues, such as acidosis, that drive BBB disruption. This perspective synthesizes groundbreaking, yet largely independent, discoveries on two key molecules: GPR68 (OGR1), a proton-sensing GPCR with unique millisecond-level mechanosensitivity to shear stress, and NINJ1, a recently defined executor of plasma membrane rupture during lytic cell death. We propose a testable novel hypothesis: that these proteins form a functional \u201cGPR68-NINJ1 axis,\u201d creating a self-amplifying mechano-chemical circuit that initiates and exacerbates BBB breakdown. We detail the molecular logic of this axis\u2014from GPR68\u2019s sensing of pathological acidosis (pH\u202f\u2264\u202f6.4) and shear stress to NINJ1\u2019s oligomerization and DAMP release\u2014and explore its potential role in unifying the pathophysiology of diverse disorders like TBI, stroke, MS, and AD. Finally, we translate this framework into a roadmap for future research and therapeutic intervention, discussing targeted inhibitors, precision chronotherapy, and the critical experiments needed to validate this emerging paradigm.<\/jats:p>","DOI":"10.3389\/fncel.2026.1757822","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:19:05Z","timestamp":1774588745000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The GPR68-NINJ1 axis: an emerging mechano-chemical checkpoint in blood\u2013brain barrier disruption\u2014a hypothetical framework and therapeutic promise"],"prefix":"10.3389","volume":"20","author":[{"given":"Boren","family":"Bai","sequence":"first","affiliation":[{"name":"International School, Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixiao","family":"Feng","sequence":"additional","affiliation":[{"name":"Gies College of Business, The University of Illinois Urbana-Champaign","place":["Urbana-Champaign, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Yang","sequence":"additional","affiliation":[{"name":"International School, Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maokui","family":"Huang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Jinan University, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuechun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medicine and Public Health, Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.bbrc.2009.07.019","article-title":"Ninjurin1 is expressed in myeloid cells and mediates endothelium adhesion in the brains of EAE rats","volume":"387","author":"Ahn","year":"2009","journal-title":"Biochem. 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