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Identifying critical elements that sustain the CSC phenotype may lead to novel strategies for cancer treatment. Here, we provide evidence of an essential link between the \u03c3<jats:sub>1<\/jats:sub> receptor (\u03c3<jats:sub>1<\/jats:sub>R), a ligand-regulated chaperone protein residing preferentially at the endoplasmic reticulum-mitochondria contact sites, and CSCs in castration-resistant prostate cancers (CRPCs). Integrating functional assays in multiple preclinical models with transcriptomic and proteomic data, we found that \u03c3<jats:sub>1<\/jats:sub>R controls CSC self-renewal capacity and tumorigenic proficiency by coordinating mitochondrial dynamics and mitochondrial-nuclear signaling. Inhibiting \u03c3<jats:sub>1<\/jats:sub>R with synthetic antagonists and RNA interference led to the progressive exhaustion and loss of tumorigenicity of the CSC progeny. Mechanistically, interfering with \u03c3<jats:sub>1<\/jats:sub>R function disrupted mitochondria homeostasis and triggered \u03b2-catenin degradation. Examining clinical CRPC samples, we found a tight correlation between \u03c3<jats:sub>1<\/jats:sub>R and mitochondrial gene expression. Furthermore, \u03c3<jats:sub>1<\/jats:sub>R and \u03b2-catenin protein levels were highly correlated in prostate tumors with significant upregulation in metastatic CRPCs, sustaining a role of the \u03c3<jats:sub>1<\/jats:sub>R-mitochondria-\u03b2-catenin axis in disease progression. This \u03c3<jats:sub>1<\/jats:sub>R-centered axis is essential for preserving the self-renewal and tumorigenic capability of CSCs and represents a critical vulnerability exploitable for discovering novel CSC-directed therapies.<\/jats:p>","DOI":"10.1038\/s41388-025-03541-7","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T17:20:57Z","timestamp":1756833657000},"page":"4032-4046","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated control of cancer stemness by \u03c31 receptor in advanced prostate cancer"],"prefix":"10.1038","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1921-161X","authenticated-orcid":false,"given":"Gianluca","family":"Civenni","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-3863","authenticated-orcid":false,"given":"Giada","family":"Sandrini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Merulla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7611-0743","authenticated-orcid":false,"given":"Carola","family":"Musumeci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8531-1864","authenticated-orcid":false,"given":"Elisa","family":"Federici","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5623-2412","authenticated-orcid":false,"given":"Arianna","family":"Vallegra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Kokanovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4400-3488","authenticated-orcid":false,"given":"Simone","family":"Mosole","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5113-3167","authenticated-orcid":false,"given":"Dheeraj","family":"Shinde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3905-647X","authenticated-orcid":false,"given":"Elisa","family":"Sorrenti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9393-9356","authenticated-orcid":false,"given":"Alyssa J. 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