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Disease progression is frequently observed as recurrence or distal metastasis. Mechanisms underlying pNEN progression are still poorly investigated, and treatments against pNEN are challenging due to the pronounced neoplastic heterogeneity. Here, by performing clinicomolecular analysis, we report a novel mechanism of positive regulatory circuit between Cav1.2\u2010mediated calcium signaling and epigenetic control by H3K27 acetylation (H3K27ac). Tumor\u2010cell\u2010specific expression of Cav1.2 strongly contributes to disease progression and correlates with malignant biological behaviors of pNEN. Moreover, we find calcium channel blockers (CCBs), especially amlodipine, remarkably inhibit pNEN progression in vitro and in vivo. Clinically, administration of CCBs correlates with better progression\u2010free survival (PFS) and a lower rate of distal metastasis. Our work uncovers the novel mechanism of the Cav1.2\u2010epigenetic circuit and expands the scope of therapeutic strategy for further investigation in pNEN.<\/jats:p>","DOI":"10.1002\/advs.202516733","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T15:43:29Z","timestamp":1770219809000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Calcium Channel Blockers Inhibit Pancreatic Neuroendocrine Neoplasms Progression via Cav1.2\u2010Epigenetic Circuit"],"prefix":"10.1002","volume":"13","author":[{"given":"Yangyinhui","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery the First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiongcong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery the First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinzhao","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery the First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingjian","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery the First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xitai","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery the First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinhao","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery the First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiawei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery the First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enliang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery the First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery the First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology &amp; 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