{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:22:30Z","timestamp":1790882550340,"version":"4.1.0"},"reference-count":74,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ateneo ex 60% G.d\u2019 Annunzio University, Chieti"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metastasis is the leading cause of cancer-related mortality. Although aspirin has been associated with reduced metastatic risk, existing evidence is fragmented across experimental systems, and a comprehensive mechanistic synthesis remains lacking. In particular, the relative contributions of platelet aggregation, thromboxane A2 (TXA2) signaling, and epithelial\u2013mesenchymal transition (EMT) to aspirin\u2019s antimetastatic effects have not been systematically integrated across preclinical and clinical studies. This systematic review was conducted in accordance with PRISMA 2020 guidelines, with the protocol registered in PROSPERO (CRD420251231581). PubMed, Scopus, and Web of Science were searched for studies published between January 2015 and December 2025, alongside ClinicalTrials.gov for completed mechanistic clinical trials. Eligible studies included in vitro, in vivo, and clinical investigations evaluating aspirin or its active metabolite in cancer-related settings and reporting mechanistic outcomes related to metastasis. Clinical studies reporting only survival or incidence outcomes without mechanistic analysis were excluded. The included studies demonstrated that aspirin suppresses metastatic dissemination across multiple cancer types through coordinated platelet-dependent and tumor-intrinsic mechanisms. Aspirin consistently inhibited platelet aggregation and COX-1-dependent TXA2 production, disrupting platelet\u2013tumor cell interactions, intravascular metastatic niche formation, and platelet-mediated immune suppression. Clinical mechanistic studies confirmed inhibition of thromboxane biosynthesis and reductions in circulating tumor cells. Beyond platelet effects, aspirin suppressed EMT, migration, and invasion through modulation of EMT transcriptional regulators and inflammatory signaling pathways. Additional mechanisms included activation of AMPK, inhibition of c-MYC signaling, regulation of redox-responsive pathways and impairment of anoikis resistance. This review provides the first integrated mechanistic synthesis of aspirin\u2019s antimetastatic actions across preclinical and clinical evidence, addressing a critical gap in understanding how platelet biology, TXA2 signaling, EMT, and tumor-intrinsic survival pathways converge in metastatic suppression. By focusing exclusively on mechanistically informative studies, this work clarifies the biological basis of aspirin\u2019s antimetastatic effects and highlights unresolved questions regarding pathway hierarchy, cancer-type specificity, and translational biomarkers, thereby informing future mechanistic and clinical investigations.<\/jats:p>","DOI":"10.3390\/ijms27031288","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T08:48:04Z","timestamp":1769590084000},"page":"1288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Anti-Metastatic Role of Aspirin in Cancer: A Systematic Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Rimsha","family":"Kanwal","sequence":"first","affiliation":[{"name":"Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, University of Chieti, 66100 Chieti, Italy"},{"name":"Unit of Clinical Pathology and Microbiology, Miulli Generale Hospital, 70021 Acquaviva delle Fonti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilal","family":"Jawed","sequence":"additional","affiliation":[{"name":"Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, University of Chieti, 66100 Chieti, Italy"},{"name":"Unit of Clinical Pathology and Microbiology, Miulli Generale Hospital, 70021 Acquaviva delle Fonti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Khuram","family":"Zakir","sequence":"additional","affiliation":[{"name":"Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, University of Chieti, 66100 Chieti, Italy"},{"name":"Unit of Clinical Pathology and Microbiology, Miulli Generale Hospital, 70021 Acquaviva delle Fonti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7817-1665","authenticated-orcid":false,"given":"Francesco","family":"Gaudio","sequence":"additional","affiliation":[{"name":"Unit of Haematology, F. MiulliUniversity Hospital, LUM University, 70021 Acquaviva delle Fonti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Martinotti","sequence":"additional","affiliation":[{"name":"Residency Program in Clinical Oncology, Faculty of Medicine, Umberto I University Hospital, University of Rome \u201cLa Sapienza\u201d, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9725-1277","authenticated-orcid":false,"given":"Matteo","family":"Botteghi","sequence":"additional","affiliation":[{"name":"Experimental Pathology Research Group, Department of Clinical and Molecular Sciences, Universita Politecnica delle Marche, 60121 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7672-891X","authenticated-orcid":false,"given":"Stefano","family":"Martinotti","sequence":"additional","affiliation":[{"name":"Unit of Clinical Pathology, Department of Medicine and Surgeon, F. 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