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PRIMA-1Met (also known as APR-246\/Eprenetapopt) is a small molecule able to restore the wild-type (wt) p53 conformation to mutant p53 proteins and to stimulate apoptosis in tumor cells; in addition, it can deplete the glutathione reservoir, increasing reactive oxygen species (ROS) production. In this study, we investigated whether combining PRIMA-1Met with Sulfasalazine (SAS), a SLC7A11\/xCT inhibitor, reduces CLL cell viability by targeting mutant p53 and the glutathione pathway. The results demonstrated that, in CLL cells, PRIMA-1Met did not restore the wt functions in the mutant p53 proteins, but it strongly reduced the antioxidant defense and induced cell death. PRIMA-1Met and SAS combination synergistically reduced cell survival regardless of p53 status and further impaired antioxidant capacity, especially in mutant p53 cells, linking their cytotoxic effect to redox imbalance. Thus, the association of PRIMA-1Met with drugs targeting the antioxidant response could represent a valid strategy to kill CLL cells carrying either wt or mutant p53.<\/jats:p>","DOI":"10.3390\/ijms26125559","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T12:53:16Z","timestamp":1749559996000},"page":"5559","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting the p53\/xCT\/GSH Axis with PRIMA-1Met Combined with Sulfasalazine Shows Therapeutic Potential in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"26","author":[{"given":"Martina","family":"Pasino","sequence":"first","affiliation":[{"name":"Neuro-Oncology and Mutagenesis Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Speciale","sequence":"additional","affiliation":[{"name":"Neuro-Oncology and Mutagenesis Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0803-1042","authenticated-orcid":false,"given":"Silvia","family":"Ravera","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3335-1101","authenticated-orcid":false,"given":"Giovanna","family":"Cutrona","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Massara","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3023-0213","authenticated-orcid":false,"given":"Serena","family":"Matis","sequence":"additional","affiliation":[{"name":"Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7077-7534","authenticated-orcid":false,"given":"Giulia Elda","family":"Valenti","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Traverso","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, 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