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Acute kidney injury (AKI) is characterized by a rapid deterioration in renal function, accompanied by a significant increase in FGF23 levels, which contribute to its severity and progression. This study investigated the mechanistic roles of G\u03b1q and G\u03b111 proteins, integral components of the lysophosphatidic acid (LPA) signaling pathway, in the regulation of FGF23 expression during AKI. Through targeted knockdown and pharmacological inhibition of G\u03b1q and G\u03b111 in the osteoblastic MC3T3\u2010E1 and osteocytic MLO\u2010Y4 cells, we demonstrated that individual suppression of these G proteins had minimal impact on both basal and LPA\u2010stimulated FGF23 levels. In contrast, concurrent knockdown significantly diminished FGF23 expression, implicating a synergistic role of G\u03b1q and G\u03b111 in FGF23 regulation. This hypothesis was supported by using G\u03b1q\/11\u2010specific inhibitors, YM\u2010254890 and FR900359, which attenuated LPA\u2010induced FGF23 upregulation. Our findings further elucidated the downstream signaling events, highlighting the involvement of PKC phosphorylation, intracellular calcium mobilization, and the MAPK\/ERK1\/2 pathway in mediating FGF23 expression. Moreover, in a folic acid\u2010induced AKI mouse model, elevated FGF23 levels in bone, bone marrow, and serum were significantly reduced following YM\u2010254890 administration, underscoring the potential of targeting G\u03b1q\/11 signaling in managing AKI\u2010associated FGF23 dysregulation. This study not only advances our understanding of FGF23 regulation in renal injuries but also identifies G\u03b1q\/11 signaling modulation as a promising strategy to alleviate AKI severity and other disorders associated with dysregulated FGF23 levels.<\/jats:p>","DOI":"10.1096\/fj.202402848rr","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T02:30:57Z","timestamp":1745548257000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["G\u03b1q\/11 Signaling Modulates Fibroblast Growth Factor 23 Production and Contributes to Acute Kidney Injury"],"prefix":"10.1096","volume":"39","author":[{"given":"Jie","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology Wuhan 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