{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T09:49:59Z","timestamp":1761212999628,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministero della Salute\u2014Ricerca Corrente 2025"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) remains a global health issue due to high incidence and mortality, complicated by limited therapeutic options and evolution of de novo resistance to conventional chemotherapy. In this study, we investigated the antiproliferative activity of RDD-142, a synthetic precursor of the HIV-1 protease inhibitor (HIV-PI) Darunavir analog, on the human hepatocellular carcinoma line (HepG2) and healthy hepatocyte line (IHH), both as a free molecule and in liposomal formulation. RDD-142 demonstrated a selective cytostatic effect on HepG2, preserving healthy IHH cells. Mechanistically, RDD-142 delayed cancer cell proliferation by attenuating the ERK1\/2 signaling pathway, and concurrently, it activated the autophagic process via p62 up-regulation. These effects were linked to RDD-142 inhibitory activity on the chymotrypsin-like subunit of the proteasome, triggering a UPR-mediated stress response. Notably, the liposomal formulation of RDD-142 significantly enhanced intracellular intake and cytotoxic efficacy. RDD-142 demonstrated promising potential as a therapeutic agent for HCC. Its antitumor activity may be further amplified through liposomal nanoformulation, offering a successful strategy to reduce effective dosage and minimize adverse effects.<\/jats:p>","DOI":"10.3390\/ijms262110305","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T09:44:30Z","timestamp":1761212670000},"page":"10305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing HIV-Protease Inhibitor Precursors as Anticancer Agents: The Synthetic Molecule RDD-142 Delays Cell Cycle Progression and Induces Autophagy in HepG2 Cells with Enhanced Efficacy via Liposomal Formulation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5712-5021","authenticated-orcid":false,"given":"Fabiana","family":"Crispo","sequence":"first","affiliation":[{"name":"Laboratory of Preclinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7937-3309","authenticated-orcid":false,"given":"Antonio","family":"Vassallo","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5274-8633","authenticated-orcid":false,"given":"Immacolata","family":"Faraone","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2580-1414","authenticated-orcid":false,"given":"Alessandro","family":"Santarsiere","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Science, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8181-9138","authenticated-orcid":false,"given":"Lucia","family":"Chiummiento","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Science, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4831-3252","authenticated-orcid":false,"given":"Mara","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6681-942X","authenticated-orcid":false,"given":"Nicoletta","family":"Cascelli","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4622-9631","authenticated-orcid":false,"given":"Xavier","family":"Fern\u00e0ndez-Busquets","sequence":"additional","affiliation":[{"name":"Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain"},{"name":"Barcelona Institute for Global Health (ISGlobal, Hospital Cl\u00ednic-Universitat de Barcelona), Rossell\u00f3 149-153, 08036 Barcelona, Spain"},{"name":"Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Mart\u00ed i Franqu\u00e8s 1, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rocchina","family":"Miglionico","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1132-8056","authenticated-orcid":false,"given":"Ilaria","family":"Nigro","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla","family":"Caddeo","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, S.P. 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