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PC1 and PC2 regulate mechanosensation, calcium signaling, and key pathways controlling tubular epithelial structure and function. Loss of PC1\/PC2 disrupts calcium homeostasis, elevates cAMP, and activates proliferative cascades such as PKA\u2013B-Raf\u2013MEK\u2013ERK, mTOR, and Wnt, driving cystogenesis via epithelial proliferation, impaired apoptosis, fluid secretion, and fibrosis. Recent evidence also implicates novel signaling axes in ADPKD progression including, the Hippo pathway, where dysregulated YAP\/TAZ activity enhances c-Myc-mediated proliferation; the stimulator of interferon genes (STING) pathway, which is activated by mitochondrial DNA release and linked to NF-\u03baB-driven inflammation and fibrosis; and the TWEAK\/Fn14 pathway, which mediates pro-inflammatory and pro-apoptotic responses via ERK and NF-\u03baB activation in tubular cells. Mitochondrial dysfunction, oxidative stress, and maladaptive extracellular matrix remodeling further exacerbate disease progression. A refined understanding of ADPKD\u2019s complex signaling networks provides a foundation for precision medicine and next-generation therapeutics. This review gathers recent molecular insights and highlights both established and emerging targets to guide targeted treatment strategies in ADPKD.<\/jats:p>","DOI":"10.3390\/cells14151203","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T15:56:16Z","timestamp":1754409376000},"page":"1203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Mechanistic Insights into the Pathogenesis of Polycystic Kidney Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Qasim","family":"Al-orjani","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubna A.","family":"Alshriem","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH 43614, USA"},{"name":"Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghad","family":"Buqaileh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neela","family":"Azizi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8226-3108","authenticated-orcid":false,"given":"Wissam","family":"AbouAlaiwi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.34067\/KID.0004522021","article-title":"Autosomal Dominant Polycystic Kidney Disease Prevalence among a Racially Diverse United States Population, 2002 through 2018","volume":"2","author":"Aung","year":"2021","journal-title":"Kidney360"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.xkme.2019.11.009","article-title":"Advances in Autosomal Dominant Polycystic Kidney Disease: A Clinical Review","volume":"2","author":"Nobakht","year":"2020","journal-title":"Kidney Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Righini, M., Mancini, R., Busutti, M., and Buscaroli, A. 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