{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:12:49Z","timestamp":1791853969416,"version":"4.3.4"},"reference-count":219,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oleocanthal (OC), a secoiridoid phenolic compound exclusive to extra virgin olive oil (EVOO), has emerged as a promising nutraceutical with multifaceted anti-cancer properties. Despite its well-characterized anti-inflammatory and antioxidant effects, the mechanistic breadth and translational potential of OC in oncology remain underexplored and fragmented across the literature. This comprehensive review synthesizes and critically analyzes recent advances in the molecular, pharmacological, and translational landscape of OC\u2019s anti-cancer activities, providing an integrative framework to bridge preclinical evidence with future clinical application. We delineate the pleiotropic mechanisms by which OC modulates cancer hallmarks, including lysosomal membrane permeabilization (LMP)-mediated apoptosis, the inhibition of key oncogenic signaling pathways (c-MET\/STAT3, PAR-2\/TNF-\u03b1, COX-2\/mPGES-1), the suppression of epithelial-to-mesenchymal transition (EMT), angiogenesis, and metabolic reprogramming. Furthermore, this review uniquely highlights the emerging role of OC in modulating drug resistance mechanisms by downregulating efflux transporters and sensitizing tumors to chemotherapy, targeted therapies, and immunotherapies. We also examine OC\u2019s bidirectional interaction with gut microbiota, underscoring its systemic immunometabolic effects. A major unmet need addressed by this review is the lack of consolidated knowledge regarding OC\u2019s pharmacokinetic limitations and drug\u2013drug interaction potential in the context of polypharmacy in oncology. We provide an in-depth analysis of OC\u2019s poor bioavailability, extensive first-pass metabolism, and pharmacogenomic interactions, and systematically compile preclinical evidence on advanced delivery platforms\u2014including nanocarriers, microneedle systems, and peptide\u2013drug conjugates\u2014designed to overcome these barriers. By critically evaluating the mechanistic, pharmacological, and translational dimensions of OC, this review advances the field beyond isolated mechanistic studies and offers a strategic blueprint for its integration into precision oncology. It also identifies key research gaps and outlines the future directions necessary to transition OC from a nutraceutical of dietary interest to a viable adjunctive therapeutic agent in cancer treatment.<\/jats:p>","DOI":"10.3390\/ijms26125521","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T03:54:18Z","timestamp":1749527658000},"page":"5521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Oleocanthal as a Multifunctional Anti-Cancer Agent: Mechanistic Insights, Advanced Delivery Strategies, and Synergies for Precision Oncology"],"prefix":"10.3390","volume":"26","author":[{"given":"Shirin","family":"Jannati","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai P.O. Box 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1326-2960","authenticated-orcid":false,"given":"Adiba","family":"Patel","sequence":"additional","affiliation":[{"name":"Birla Institute of Technology & Science, Pilani\u2014Dubai Campus (BITS Pilani, Dubai Campus), Dubai International Academic City, Dubai P.O. Box 345055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajashree","family":"Patnaik","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai P.O. Box 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7546-8893","authenticated-orcid":false,"given":"Yajnavalka","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai P.O. Box 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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