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Necroptosis, a controlled type of necrosis, is now recognized as an appealing alternative for overcoming apoptotic resistance and increasing therapeutic effectiveness. This kind of cell death is coordinated by key mediators such as receptor\u2010interacting protein kinases (RIPK1, and RIPK3) and mixed lineage kinase domain\u2010like protein (MLKL), which together modulate inflammatory cascades and immunological responses. However, necroptosis plays a paradoxical role in cancer, acting both as a tumor suppressor and a driver of metastasis. To disentangle the remaining riddles regarding necroptosis in cancer, a deeper understanding of its mechanism, physiological and pathological activities is desperately needed. This review addresses the innovative approach of targeting necroptosis as a new way to combat apoptosis resistance in tumor therapy, and it summarizes the latest data on its connection with cancer. In the last few decades, phytochemicals have gained plenty of attention for their potential to influence necroptotic pathways, which opens up new options for oncological therapies. Phenolics, alkaloids, and terpenoids are instances of bioactive compounds that possess resilient anti\u2010cancer potential through oxidative stress induction and RIPK1\/RIPK3\u2010dependent necroptotic signaling activation. The evidence of phytochemical\u2010induced necroptosis is methodically amalgamated in this review. An in\u2010depth literature search across five leading databases culminated in a shortlist of 314 meticulously vetted articles. This review emphasizes the therapeutic potential of necroptosis\u2010inducing phytochemicals, delineates molecular breakthroughs, and addresses the barriers regarding clinical application.<\/jats:p>","DOI":"10.1002\/ptr.70322","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:11:11Z","timestamp":1775625071000},"page":"3628-3667","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Comprehensive Review on Necroptosis Inducing Phytochemicals for Cancer Therapy: Preclinical Evidence"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4480-6898","authenticated-orcid":false,"given":"Bhuvaneshwari","family":"Deivendran","sequence":"first","affiliation":[{"name":"Molecular Toxicology Laboratory, Department of Biotechnology Bharathiar University  Coimbatore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9777-4242","authenticated-orcid":false,"given":"Suryaa","family":"Manoharan","sequence":"additional","affiliation":[{"name":"Molecular Toxicology Laboratory, Department of Biotechnology Bharathiar University  Coimbatore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2159-8198","authenticated-orcid":false,"given":"Ekambaram","family":"Perumal","sequence":"additional","affiliation":[{"name":"Molecular Toxicology Laboratory, Department of Biotechnology Bharathiar University  Coimbatore India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0889\u20108588(05)70012\u20105"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25052631"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.12332"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.3906\/sag\u20102005\u2010327"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13194820"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/2052\u20108426\u20102\u201027"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222111781"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes8020076"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2017.1338684"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12051301"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19071930"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jarmap.2016.01.002"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21093125"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116123"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.4103\/0971\u20106866.120811"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2015.00009"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495\u2010016\u20101333\u20103"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9061894"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/74710"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11071221"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11172734"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555\u2010019\u201009803\u20107"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26051936"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2015.06.011"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022016022"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2015.69"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0889\u20108588(05)70014\u20109"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.434"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10565\u2010022\u201009774\u20106"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.21\u20105\u2010610"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0000000000000551"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.3550"},{"key":"e_1_2_13_34_1","first-page":"1244","article-title":"Specific Immune Cell Therapy Against Ovarian Cancer In\u00a0Vivo and In\u00a0Vitro","volume":"27","author":"Chang X. 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