Potential Biological Targets of Anticancer Metal‐Based Drug Candidates: A Systematic Review

The discovery of Cisplatin marked the beginning of the metallodrug era in oncology. Despite their clinical success, platinum-based 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-related 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-directed 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-based biological processes, revealing recurrent associations with redox regulation, apoptosis and cell-cycle control, and DNA replication and repair, with fewer studies addressing angiogenesis and drug-resistance 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-related cellular networks, particularly those associated with redox balance and stress-response pathways. However, the available literature remains largely preclinical and mechanistically heterogeneous, highlighting the need for more rigorous target-validation strategies to clarify the therapeutic relevance of proposed protein targets.