{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:45:15Z","timestamp":1785422715281,"version":"3.56.0"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32070532"],"award-info":[{"award-number":["32070532"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32070532"],"award-info":[{"award-number":["32070532"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) that emerges under androgen deprivation and is associated with therapeutic resistance. The contribution of volume-regulated anion channels (VRACs) to this process remains poorly understood. This study identified leucine-rich repeat-containing 8 subunit D (LRRC8D), a VRAC subunit, as the only family member consistently downregulated in NEPC and associated with neuroendocrine (NE)-like features. LRRC8D downregulation was accompanied by suppression of swelling-activated VRAC currents, increased synaptophysin (SYP) expression, decreased cisplatin sensitivity, and neurosecretory remodeling. Conversely, LRRC8D overexpression enhanced cisplatin-induced apoptosis, reduced colony formation, and suppressed tumor growth in xenograft models, including under cisplatin treatment. Consistent alterations in LRRC8D and SYP expression were also observed in enzalutamide-resistant patient-derived organoids. Mechanistically, RE1-silencing transcription factor (REST) promoted LRRC8D transcription. Functional analyses further demonstrated that CAV-1 acted upstream of LRRC8D, and LRRC8D negatively regulated STAT3 activation. Together, these findings indicate that LRRC8D influences PCa phenotype and platinum responsiveness, and implicate a regulatory axis involving LRRC8D and CAV-1\/STAT3 signaling in NE-associated features of advanced PCa. Functional analyses further showed that CAV-1 acted upstream of LRRC8D, and LRRC8D negatively regulated STAT3 activation. Together, these findings indicate that LRRC8D influences PCa phenotype and platinum responsiveness and implicate a regulatory axis involving LRRC8D and CAV-1\/STAT3 signaling in NE-associated features of advanced PCa.<\/jats:p>","DOI":"10.3390\/membranes16060198","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T07:43:02Z","timestamp":1780904582000},"page":"198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["LRRC8D Suppresses Prostate Cancer Growth and Enhances Platinum Sensitivity via Modulation of CAV-1\/STAT3 Signaling"],"prefix":"10.3390","volume":"16","author":[{"given":"Rong","family":"Xu","sequence":"first","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"},{"name":"Department of Geriatrics, Xijing Hospital, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Shui","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"},{"name":"Department of Pathology, The First Affiliated Hospital of the Army Medical University, Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Han","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzi","family":"Xing","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiqin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengpeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengxu","family":"Tan","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Qin","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9671-6358","authenticated-orcid":false,"given":"Xiaoming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Xijing Hospital, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7490-3593","authenticated-orcid":false,"given":"Changhong","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, Laboratory Animal Center, The Air Force Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.semcancer.2022.05.007","article-title":"Molecular mechanisms underlying the development of neuroendocrine prostate cancer","volume":"86","author":"Liu","year":"2022","journal-title":"Semin. 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