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Cisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties, namely the onset of resistance to the drug and the cytotoxic effect in patients. Here, we used Caenorhabditis elegans to investigate factors influencing the response to cisplatin in multicellular organisms. In this hermaphroditic model organism, we observed that sperm failure is a major cause of cisplatin-induced infertility. RNA sequencing data indicate that cisplatin triggers a systemic stress response, in which DAF-16/FOXO and SKN-1/NRF2, two conserved transcription factors, are key regulators. We determined that inhibition of the DNA damage-induced apoptotic pathway does not confer cisplatin protection to the animal. However, mutants for the pro-apoptotic BH3-only gene ced-13 are sensitive to cisplatin, suggesting a protective role of the intrinsic apoptotic pathway. Finally, we demonstrated that our system can also be used to identify mutations providing resistance to cisplatin and therefore potential biomarkers of innate cisplatin-refractory patients. We show that mutants for the redox regulator trxr-1, ortholog of the mammalian thioredoxin reductase 1 TRXR1, display cisplatin resistance. By CRISPR/Cas9, we determined that such resistance relies on the presence of the single selenocysteine residue in TRXR-1. ; This study was supported by grants from the Instituto de Salud Carlos III (ISCIII; PI15/00895 to J.C., PI16/01898 to A.V.), which is co-funded by the European Regional Development Fund/FEDER. The A.V. laboratory was also supported by funding from Ministerio de Economía y Competitividad (BFU2007-67123). M.B. was supported by a Netherlands Organization for Scientific Research (NWO) chemical sciences ECHO grant (711.014.005). E.N. was supported a Sociedad Española de Oncología Médica (SEOM) grant for emerging research groups. F.J.G.-R. was the recipient of a PFIS predoctoral fellowship from ISCIII. A.M.-V. was supported by a grant from Ministerio de Economía y Competitividad (BFU2015-64408-P, co-financed by the European Social Fund) and is a member of the EU-ROS Cost Action of the European Union. J.C., M.B., S.H. and A.M.-V are members of the GENIE EU Cost action. D.B. was recipient of a Consejo Nacional de Ciencia y Tecnología 'al extranjero' fellowship (523048). ; Peer reviewed