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Although PARP inhibitors like Olaparib have shown efficacy in BRCA-mutated cancers, their benefit is limited in broader patient populations. <jats:italic>TP53<\/jats:italic> mutations, highly prevalent in ovarian cancer, promote tumor progression and resistance, making p53 a key therapeutic target. This study evaluated the anticancer potential of HO-3867, a curcumin analog known to restore mutant p53 function, alone and in combination with Olaparib. We used fallopian tube-derived ovarian cancer models harboring mutant or null <jats:italic>TP53<\/jats:italic> and analyzed <jats:italic>TP53<\/jats:italic> expression and mutation profiles using TCGA datasets. Molecular docking simulations and cellular thermal shift assays (CETSA) confirmed HO-3867 binding to the p53<jats:sup>Y220C<\/jats:sup> mutant core domain. Cytotoxicity was assessed via SRB assays; flow cytometry and Western blotting were used to examine cell cycle progression, apoptosis, and DNA damage. HO-3867 treatment increased phospho-p53 (Ser15) and p21 expression, induced G1 phase arrest, and suppressed cell viability. Notably, co-treatment with Olaparib synergistically enhanced apoptosis, as indicated by increased caspase-3 and PARP1 cleavage and elevated \u03b3H2AX levels. These findings suggest that HO-3867 reactivates mutant p53 and potentiates Olaparib efficacy by promoting apoptosis and amplifying DNA damage, offering a promising therapeutic strategy for <jats:italic>TP53<\/jats:italic>-mutant ovarian cancer.<\/jats:p>","DOI":"10.1007\/s10637-025-01571-2","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T23:59:45Z","timestamp":1754351985000},"page":"857-873","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic effects of the curcumin analog HO-3867 and olaparib in transforming fallopian tube epithelial cells"],"prefix":"10.1007","volume":"43","author":[{"given":"Cai-Chieh","family":"Tseng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min-Hsi","family":"Ku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Min","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ava","family":"Mendez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tessa","family":"Christner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Chieh","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Lun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Hsiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Wen","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johnathan","family":"Barefoot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Wei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"issue":"1","key":"1571_CR1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A (2024) Cancer statistics, 2024. 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