{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:55:21Z","timestamp":1785164121875,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007109","name":"University of Ferrara","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007109","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fondo di Ateneo per la Ricerca Scientifica"},{"name":"Fondazione Di Bella L.M.N"},{"name":"Fondo per l\u2019incentivazione alla Ricerca Dipartimentale (FIRD 2022) M.S."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>While the PI3K\/Akt\/mTOR pathway is a well-established drug target in T-cell acute lymphoblastic leukemia (T-ALL), the contribution of the Hedgehog (Hh) pathway in T-ALL malignancy remains poorly defined. We investigated the effects of pharmacological inhibition of key signaling nodes in these pathways using T-ALL cell lines (Jurkat, Molt-4, DND-41, and ALL-SIL). Cells were treated with the Gli1 inhibitor Gant-61, the Smoothened inhibitors GDC-0449 and Glasdegib, the Akt inhibitor MK-2206, and the mTOR inhibitor RAD001, both alone and in combination. Analyses of cell viability, cell cycle progression, apoptosis, autophagy, protein expression, and in situ intracellular distribution revealed potent cytotoxic activity of Gant-61 and MK-2206, while Smo and mTOR inhibitors showed limited efficacy. Combined Gli1 and Akt inhibition induced synergistic suppression of proliferation, enhanced G0\/G1 arrest, increased apoptosis, and promoted autophagy, accompanied by reduced nuclear Gli1 and decreased Akt phosphorylation. These findings demonstrate a functional interaction between Hh\/Gli1 and PI3K\/Akt pathways in T-ALL and identify Gli1 as a critical, druggable node. Dual targeting of Gli1 and Akt represents a potential therapeutic strategy to overcome resistance and improve treatment outcomes in T-ALL.<\/jats:p>","DOI":"10.3390\/cells14241972","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T12:57:41Z","timestamp":1765457861000},"page":"1972","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual Hedgehog\/GLI1 and PI3K\/Akt\/mTOR Targeting Possesses Higher Efficacy to Inhibit T-Cell Acute Lymphoblastic Leukemia Growth"],"prefix":"10.3390","volume":"14","author":[{"given":"Marica","family":"De Chiara","sequence":"first","affiliation":[{"name":"Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3996-3667","authenticated-orcid":false,"given":"Mariaconcetta","family":"Sicurella","sequence":"additional","affiliation":[{"name":"Department of Environmental Sciences and Prevention, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3987-7267","authenticated-orcid":false,"given":"Mattia","family":"Melloni","sequence":"additional","affiliation":[{"name":"Department of Chemical, Pharmaceutical, and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7276-3168","authenticated-orcid":false,"given":"Ilaria","family":"Conti","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7924-1477","authenticated-orcid":false,"given":"Luca Maria","family":"Neri","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy"},{"name":"LTTA-Electron Microscopy Center, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/MOP.0000000000000310","article-title":"New advances and future directions in pediatric hematology\/oncology","volume":"28","author":"Raetz","year":"2016","journal-title":"Curr. 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