{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:01:53Z","timestamp":1790776913751,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82330094,U25A20122"],"award-info":[{"award-number":["82330094,U25A20122"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFF1501304"],"award-info":[{"award-number":["2024YFF1501304"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013105","name":"Shanghai Rising-Star Program","doi-asserted-by":"publisher","award":["23QC1401400"],"award-info":[{"award-number":["23QC1401400"]}],"id":[{"id":"10.13039\/501100013105","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai Municipality","doi-asserted-by":"publisher","award":["23ZR1441300"],"award-info":[{"award-number":["23ZR1441300"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:bold>Background<\/jats:bold>\n                    : Everolimus (EVE) is a key treatment for advanced clear cell renal cell carcinoma (ccRCC), mainly targeting AKT\/mTOR signaling. However, developed resistance remains a major challenge for EVE treatment. Aberrant alternative splicing, particularly regulated by PTBP1, may represent a critical mechanism enabling the activation of these resistance\u2010associated pathways.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods<\/jats:bold>\n                    : Single\u2010cell transcriptome sequencing is performed to reveal the association between PTBP1 expression, EVE resistance and AKT\/mTOR pathway activity. Patient\u2010derived specimens, animal models, and in vitro assays are used to evaluate the role of PTBP1 in EVE resistance. Full\u2010length transcriptome sequencing and crosslinking immunoprecipitation (CLIP) sequencing are employed to identify PTBP1\u2010regulated splicing targets. Co\u2010immunoprecipitation, proteomic analyses, and molecular docking further elucidate the mechanism by which DNAJB6b re\u2010activated AKT\/mTOR signaling.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results<\/jats:bold>\n                    : PTBP1 is upregulated in EVE\u2010resistant tumors and its expression positively correlates with AKT\/mTOR signaling activation. PTBP1 promotes the expression of the DNAJB6b isoform through alternative splicing. EIF4B is identified as a direct binding partner of DNAJB6b, forming a complex that enhances oncogenic translation and activates a PKIB\u2010dependent AKT\/mTOR signaling cascade.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusion<\/jats:bold>\n                    : This study demonstrates that PTBP1 drives EVE resistance in ccRCC by upregulating DNAJB6b, which recruits EIF4B to initiate a PKIB\/AKT\/mTOR positive feedback loop, sustaining oncogenic translation and therapeutic evasion.\n                  <\/jats:p>","DOI":"10.1002\/advs.77782","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PTBP1\u2010Mediated Alternative Splicing of DNAJB6 Promotes Everolimus Resistance in Clear Cell Renal Cell Carcinoma via EIF4B\/PKIB\/AKT\/mTOR Positive Feedback Loop"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5268-0886","authenticated-orcid":false,"given":"Xiu\u2010wu","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Urology Xinhua Hospital School of Medicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6698-1549","authenticated-orcid":false,"given":"Hong\u2010feng","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Urology Xinhua Hospital School of Medicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mu\u2010chen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology Xinhua Hospital School of Medicine Shanghai Jiao Tong University  Shanghai 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