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Despite their clinical success, platinum\u2010based compounds present important limitations, including drug resistance and systemic toxicity. These challenges have stimulated interest in alternative metal complexes capable of interacting with biomolecular targets beyond DNA, particularly proteins involved in cancer\u2010related pathways. To systematically identify and categorize protein targets associated with the antitumor activity of metal complexes in preclinical studies, emphasizing their functional classification and biological relevance. A systematic search was conducted in Web of Science, Wiley, Scopus, and ScienceDirect for studies published between January 2015 and March 2025. Original studies evaluating the antitumor activity of metal complexes with experimental or computational evidence of protein\u2010directed mechanisms were included. Reviews, editorials, theoretical studies without experimental support, and studies focused exclusively on serum albumin binding were excluded. Of the 873 records identified, 59 studies met the inclusion criteria. Reported targets were organized according to Gene Ontology\u2013based biological processes, revealing recurrent associations with redox regulation, apoptosis and cell\u2010cycle control, and DNA replication and repair, with fewer studies addressing angiogenesis and drug\u2010resistance mechanisms. Across categories, mechanistic evidence is predominantly derived from in vitro assays and computational analyses, with limited demonstration of selective intracellular target engagement. Current evidence indicates that metal complexes frequently perturb survival\u2010related cellular networks, particularly those associated with redox balance and stress\u2010response pathways. However, the available literature remains largely preclinical and mechanistically heterogeneous, highlighting the need for more rigorous target\u2010validation strategies to clarify the therapeutic relevance of proposed protein targets.<\/jats:p>","DOI":"10.1002\/ddr.70315","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T09:12:44Z","timestamp":1779095564000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Potential Biological Targets of Anticancer Metal\u2010Based Drug Candidates: A Systematic Review"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6253-0846","authenticated-orcid":false,"given":"Allysson L. dos S.","family":"Ferreira","sequence":"first","affiliation":[{"name":"Graduate Program in Biosciences Federal University of Vale do S\u00e3o Francisco Petrolina Pernambuco Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8807-1601","authenticated-orcid":false,"given":"Bruna B.","family":"Dantas","sequence":"additional","affiliation":[{"name":"Academic Health Unit\/Center for Education and Health Federal University of Campina Grande Cuit\u00e9 Para\u00edba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7757-7209","authenticated-orcid":false,"given":"Jailton De","family":"Souza\u2010Ferrari","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Center for Exact and Natural Sciences Federal University of Para\u00edba, Campus I Castelo Branco Para\u00edba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1000-0114","authenticated-orcid":false,"given":"Edilson B. 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