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GPR68 primarily modulates inflammatory responses through the Gq\/11\u2013phospholipase C\u2013inositol 1,4,5-trisphosphate\/Ca<jats:sup>2+<\/jats:sup> signaling axis. Extracellular acidification first promotes GPR68 coupling with Gq\/11, subsequently enhancing phospholipase C\u03b2 activity and increasing IP<jats:sub>3<\/jats:sub> production; IP<jats:sub>3<\/jats:sub> then mediates Ca<jats:sup>2+<\/jats:sup> release from the endoplasmic reticulum, activating calmodulin-dependent kinase and calcineurin, ultimately inducing NF-\u03baB and NFAT nuclear translocation to upregulate inflammatory mediators such as IL-6, TNF-\u03b1, and COX-2. This cascade activates inflammatory signaling pathways, thereby driving cellular and tissue senescence and creating favorable conditions for the progression of age-related diseases. However, its long-term causal relationship requires further validation through prospective studies. Abnormal GPR68 expression is closely associated with chronic inflammation, acidosis, and fibrosis in diseases including osteoarthritis, atherosclerosis, chronic kidney disease, Alzheimer\u2019s disease, Parkinson\u2019s disease, glioblastoma (GBM), and pancreatic cancer. In GBM, knocking down GPR68 or using the GPR68 inhibitor ogremorphin significantly reduces tumor cell survival. Despite its potential as a therapeutic target, challenges remain, such as the unresolved crystal structure, the lack of <jats:italic>in vivo<\/jats:italic> causality, cell-type specificity, and context-dependent signaling mechanisms. Targeting GPR68 may offer novel therapeutic strategies for these pathological processes.<\/jats:p>","DOI":"10.3389\/fragi.2025.1684450","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T09:32:16Z","timestamp":1760952736000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Acid sensing to inflammaging: mechanisms and therapeutic promise of GPR68 (OGR1) in aging-related diseases"],"prefix":"10.3389","volume":"6","author":[{"given":"Jianlei","family":"Wei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxin","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zebin","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengxia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1016\/j.cellsig.2006.01.005","article-title":"Sphingosylphosphorylcholine enhances calcium entry in thyroid FRO cells by a mechanism dependent on protein kinase C","volume":"18","author":"Afrasiabi","year":"2006","journal-title":"Cell. 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