Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer affecting the pleural lining of the lungs. SETD2 is mutated in a subset of MPM patients and result in dependency on KDM4A . Preliminary studies revealed overexpression of KDM4A is also highly expressed in MPM cell lines and patient samples. Furthermore, TCGA data analysis suggested that MPM has the highest relative KDM4A expression compared to other cancer types. KDM4A , lysine histone demethylase 4A, regulates demethylation of H3K36me3 and H3K9me3 and, known to regulate apoptosis, DNA repair, splicing, self-renewal and other biological processes in cancer development. However, the role of KDM4A in MPM is not fully understood. In the present study, we aimed to define the role of KDMA4 in MPM. Transcriptomic analysis following the down regulation of KDM4A resulted in reactivation of innate immune response gene expression including the interferon gamma stimulatory genes (ISG's), and inhibition of WNT pathway target gene expression suggesting a crosstalk between KDM4A and WNT signaling pathway. We also observed a decrease in expression of genes involved in DNA repair including HR, mismatch and BER mechanisms. Dual inhibition of KDM4A and WNT pathway exhibited synergy in MPM cell lines. Chromatin Immunoprecipitation-seq (ChIP-seq) revealed increased deposition of H3K9me3 on multiple KDM4A target genes as expected including the DNA repair genes and WNT target genes upon knockdown of KDM4A. Treatment with KDM4A specific inhibitors resulted in cell death and regulated WNT pathway target genes, suggesting that combining KDM4A-targeted therapy with WNT targeting inhibitors and/or CHK1/2 inhibitors could potentially benefit MPM patients. Inhibition of KDM4A resulted in decreased tumor growth in patient derived xenografts. Thus, targeting KDM4A opens new avenues for therapeutic approaches in MPM patients with poor prognosis and potentially increase survival.