{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T05:14:28Z","timestamp":1783314868941,"version":"3.54.6"},"reference-count":252,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Cancer remains one of the leading causes of morbidity and mortality worldwide, imposing substantial clinical, societal, and economic burdens. Despite major advances in surgical oncology, systemic chemotherapy, radiation therapy, molecularly targeted therapeutics, and immune checkpoint inhibition, contemporary cancer treatment remains constrained by dose-limiting toxicities, intratumoral and intertumoral heterogeneity, and the inexorable emergence of multifaceted drug resistance mechanisms. These persistent therapeutic challenges have reinstated interest in natural products (NPs) as evolutionarily refined sources of anticancer agents characterized by structurally diverse molecular targets and pleiotropic mechanisms of action. Indeed, a substantial proportion of currently approved anticancer drugs are either directly derived from or structurally inspired by natural compounds. This comprehensive review examines the role of NPs as anticancer agents, with particular emphasis on bioactive compounds isolated from plants, fungi, marine organisms, and environmental bacteria indigenous to the Middle East and North Africa (MENA) region. We summarize exemplary MENA-derived NPs demonstrating cytotoxic, antiproliferative, pro-apoptotic, anti-angiogenic, anti-metastatic, and immunomodulatory activities across a wide range of preclinical cancer models. Mechanistically, these compounds converge on critical oncogenic signaling networks, including p53-caspase apoptotic cascades, NF-\u03baB transcriptional inhibition, reactive oxygen species modulation, cell-cycle arrest, epigenetic reprogramming, and suppression of tumor invasion and chronic inflammation. In parallel, we highlight transformative technological innovations\u2014including high-throughput phenotypic and biochemical screening platforms, metagenomics, genome mining algorithms, biosynthetic gene cluster activation, and synthetic biology approaches\u2014that are fundamentally reshaping NP discovery and enabling access to previously cryptic or unculturable microbial biosynthetic pathways. These methodological advances, coupled with multi-omics integration, artificial intelligence-driven compound prediction, and heterologous expression systems, are accelerating the identification and characterization of structurally novel anticancer agents. Collectively, the evidence presented underscores the MENA region as a significantly underexplored yet exceptionally promising biodiverse reservoir of anticancer NPs with substantial therapeutic potential. Strategic harnessing of this biodiversity through interdisciplinary collaborative research, ethically governed bioprospecting frameworks, and translational development pipelines may yield structurally innovative, mechanistically distinct, and potentially safer therapeutic modalities to complement existing cancer treatments and address critical unmet clinical needs in precision oncology.<\/jats:p>","DOI":"10.3389\/fonc.2026.1846357","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T04:21:16Z","timestamp":1783311676000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Anticancer natural products from the Middle East and North Africa: biodiversity, mechanisms, and translational challenges"],"prefix":"10.3389","volume":"16","author":[{"given":"Razane","family":"Hamiyeh","sequence":"first","affiliation":[{"name":"Department of Experimental Pathology, Immunology and Microbiology, 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Beirut","place":["Beirut, Lebanon"]},{"name":"Center for Drug Discovery, American University of Beirut","place":["Beirut, Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wassim","family":"Abou-Kheir","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut","place":["Beirut, Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural products as sources of new drugs over the nearly four decades from 01\/1981 to 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