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However, while organic small molecules have been extensively studied for this purpose, metal-based compounds have received relatively little attention as triggers of necroptosis. The development of ruthenium (II) hybrid compounds, particularly those containing triazene (Ru-TRZ), highlights a novel avenue for modulating necroptotic cell death. Here we show that incorporating a methyltriazene moiety, a known alkylating warhead, confers superior mitochondrial-targeting properties and enhances cell death compared to amide-containing counterparts. Ru-hybrid TRZ2 exhibits also antitumor efficacy against in vivo drug-resistant cancer cells. Mechanistically, we demonstrate that Ru-TRZ hybrids induce apoptosis. In addition, by activating downstream RIPK3-driven cell death, TRZ2 proficiently restrains normal mitochondrial function and activity, leading to cancer cell necroptosis. Finally, TRZ2 synergizes anti-proliferative activity and cell death effects induced by conventional drugs. In conclusion, Ru-TRZ2 stands as a promising ruthenium-based chemotherapeutic agent inducing necroptosis in drug resistant cancer cells.<\/jats:p>","DOI":"10.1038\/s41420-024-02033-z","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T21:04:16Z","timestamp":1716930256000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Necroptosis induced by ruthenium (II) complexes as mitochondrial disruptors"],"prefix":"10.1038","volume":"10","author":[{"given":"Joana","family":"Gon\u00e7alves","sequence":"first","affiliation":[]},{"given":"Joana D.","family":"Amaral","sequence":"additional","affiliation":[]},{"given":"Rita","family":"Capela","sequence":"additional","affiliation":[]},{"given":"Maria de Jesus","family":"Perry","sequence":"additional","affiliation":[]},{"given":"Cl\u00e1udia","family":"Braga","sequence":"additional","affiliation":[]},{"given":"Maria Manuela","family":"Gaspar","sequence":"additional","affiliation":[]},{"given":"F\u00e1tima M.","family":"Piedade","sequence":"additional","affiliation":[]},{"given":"Lubertus","family":"Bijlsma","sequence":"additional","affiliation":[]},{"given":"Antoni","family":"Roig","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3205-9459","authenticated-orcid":false,"given":"Sandra N.","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Moreira","sequence":"additional","affiliation":[]},{"given":"Pedro","family":"Florindo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4829-754X","authenticated-orcid":false,"given":"Cec\u00edlia M. 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