{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T08:48:13Z","timestamp":1788684493459,"version":"build-2803163510"},"reference-count":87,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["ECS00000041"],"award-info":[{"award-number":["ECS00000041"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Sapienza University Ateneo","award":["RP123188F3E745A7"],"award-info":[{"award-number":["RP123188F3E745A7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hormone-independent breast and prostate cancers represent highly aggressive malignancies characterized by profound metabolic reprogramming, elevated oxidative stress, and loss of sensitivity to endocrine therapies. Increasing evidence indicates that tumor progression and metabolic plasticity are sustained by interconnected signaling networks linking transcriptional regulation to energy metabolism. Among these, the STAT3\u2013PKM2\u2013HIF-1\u03b1 signaling axis, functionally reinforced by reactive oxygen species (ROS), has been proposed as a central regulator of the Warburg phenotype and cellular adaptation to adverse microenvironmental conditions. Using androgen-independent prostate cancer (DU145) and triple-negative breast cancer (KPL-4) cell lines, we demonstrated constitutive activation and reciprocal regulation of STAT3, PKM2, and HIF-1\u03b1. Pharmacological inhibition of STAT3, stabilization of tetrameric PKM2 by L-serine, and ROS scavenging with N-acetylcysteine significantly reduced STAT3 phosphorylation, PKM2 nuclear translocation, and HIF-1\u03b1 stabilization. These molecular effects were accompanied by decreased intracellular ROS levels, reduced lactate production, increased pyruvate levels, and a metabolic shift toward oxidative phosphorylation. Functionally, treated cells exhibited reduced Ki-67 expression and impaired clonogenic capacity. Our results identify the STAT3\u2013PKM2\u2013HIF-1\u03b1\/ROS axis as a key determinant of metabolic and phenotypic plasticity in hormone-independent breast and prostate cancers, highlighting its potential as a molecular target for therapeutic modulation of cancer-associated metabolic phenotypes.<\/jats:p>","DOI":"10.3390\/ijms27052357","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T12:48:56Z","timestamp":1772542136000},"page":"2357","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ROS-Fueled Allies: STAT3, PKM2, and HIF-1\u03b1 Influencing Energy Metabolism in Hormone-Independent Cancers"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4864-4350","authenticated-orcid":false,"given":"Sara","family":"Fiorini","sequence":"first","affiliation":[{"name":"Department of Biochemical Science \u201cA. Rossi Fanelli\u201d, Faculty of Pharmacy and Medicine, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Maras","sequence":"additional","affiliation":[{"name":"Department of Biochemical Science \u201cA. Rossi Fanelli\u201d, Faculty of Pharmacy and Medicine, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9238-132X","authenticated-orcid":false,"given":"Giuseppina","family":"Mignogna","sequence":"additional","affiliation":[{"name":"Department of Biochemical Science \u201cA. Rossi Fanelli\u201d, Faculty of Pharmacy and Medicine, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4294-9866","authenticated-orcid":false,"given":"Monia","family":"Perugini","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Agro-Food and Environmental Technology, University of Teramo, Campus \u201cAurelio Saliceti\u201d, Via R. Balzarini 1, 64100 Teramo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Retali","sequence":"additional","affiliation":[{"name":"Department of Biochemical Science \u201cA. Rossi Fanelli\u201d, Faculty of Pharmacy and Medicine, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Meschiari","sequence":"additional","affiliation":[{"name":"Department of Biochemical Science \u201cA. 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