{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:11:15Z","timestamp":1790014275104,"version":"4.0.1"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373103"],"award-info":[{"award-number":["82373103"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Science and Technology of Shaanxi Province","award":["2024SF-YBXM-192"],"award-info":[{"award-number":["2024SF-YBXM-192"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    p21-Activated kinase 4 (PAK4) is widely dysregulated and acts as an oncogene in multiple cancers, and the inhibition or knockout of PAK4 has shown excellent therapeutic effects in inhibiting tumor progression in combination with immunotherapy across a variety of cancers. Previously, we reported our self-developed peptide proteolysis-targeting chimera (PROTAC) drug PpD, which specifically and selectively degrades the PAK4 protein to effectively inhibit the growth of renal cancer tumors. In this study, we confirmed that the PAK4 protein is highly expressed in bladder cancer (BLCA) tissues. Moreover, we established PAK4 knockout BLCA cell lines and explored the regulatory mechanisms of PAK4 in BLCA via RNA sequencing. Our RNA sequencing results revealed that PAK4 promotes the cell cycle progression of BLCA cells and inhibits apoptosis. Comparative studies of the PAK4 knockout cell lines T-24 sg\/PAK4 and 5637 sg\/PAK4 with PpD drug treatment revealed that both PAK4 knockout and PpD drug treatment inhibited the ERK1\/2\/CDK4 pathway, thereby blocking the cell cycle transition from the G1 phase to the S phase, and both induced caspase-3-mediated apoptotic cell death.\n                    <jats:italic>In vivo<\/jats:italic>\n                    animal experiments also confirmed that the growth of BLCA cells was significantly inhibited in both the PAK4 knockout group and the PpD drug-treated group. Collectively, our findings indicate that PpD exhibits potent anti-tumor activity against BLCA and holds promising potential for therapeutic application in other cancers.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0358561","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T17:34:44Z","timestamp":1790012084000},"page":"e0358561","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["PAK4-targeting PROTAC inhibits bladder cancer cell proliferation"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7557-2829","authenticated-orcid":true,"given":"Shan","family":"Xu","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"],"department":["Department of Urology"]},{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The 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Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenkun","family":"Ma","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"],"department":["Department of Urology"]},{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Bai","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"],"department":["Department of Urology"]},{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, 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