Ruthenium complexes are considered as potential replacements for platinumcompounds in oncotherapy. Their clinical development is handicapped by a lackof consensus on their mode of action. In this study, we identify three histones(H3.1, H2A, H2B) as possible targets for an anticancer redox organorutheniumcompound (RDC11). Using puriied histones, we conirmed an interaction betweenthe ruthenium complex and histones that impacted on histone complex formation.A comparative study of the ruthenium complex versus cisplatin showed differentialepigenetic modiications on histone H3 that correlated with differential expressionof histone deacetylase (HDAC) genes. We then characterized the impact of theseepigenetic modiications on signaling pathways employing a transcriptomicapproach. Clustering analyses showed gene expression signatures speciic forcisplatin (42%) and for the ruthenium complex (30%). Signaling pathway analysespointed to speciicities distinguishing the ruthenium complex from cisplatin. Forinstance, cisplatin triggered preferentially p53 and folate biosynthesis while theruthenium complex induced endoplasmic reticulum stress and trans-sulfurationpathways. To further understand the role of HDACs in these regulations, we usedsuberanilohydroxamic acid (SAHA) and showed that it synergized with cisplatincytotoxicity while antagonizing the ruthenium complex activity. This study providescritical information for the characterization of signaling pathways differentiatingboth compounds, in particular, by the identiication of a non-DNA direct target foran organoruthenium complex.