Setlai, Botle PreciousMkhize-Kwitshana, Zilungile LynetteMehrotra, RaviMulaudzi, Thanyani VictorDlamini, Zodwa2022-12-142022-12-142022-08-12Setlai, B.P.; MkhizeKwitshana, Z.L.; Mehrotra, R.; Mulaudzi, T.V.; Dlamini, Z. Microbiomes, Epigenomics, Immune Response, and Splicing Signatures Interplay: Potential Use of Combination of Regulatory Pathways as Targets for Malignant Mesothelioma. International Journal of Molecular Sciences. 2022, 23, 8991. https://doi.org/10.3390/ijms23168991.1422-0067 (online)1661-6596 (print)10.3390/ijms23168991https://repository.up.ac.za/handle/2263/88784Malignant mesotheliomas (MM) are hard to treat malignancies with poor prognosis and high mortality rates. This cancer is highly misdiagnosed in Sub-Saharan African countries. According to literature, the incidence of MM is likely to increase particularly in low-middle-income countries (LMICs). The burden of asbestos-induced diseases was estimated to be about 231,000 per annum. Lack of awareness and implementation of regulatory frameworks to control exposure to asbestos fibers contributes to the expected increase. Exposure to asbestos fibers can lead to cancer initiation by several mechanisms. Asbestos-induced epigenetic modifications of gene expression machinery and non-coding RNAs promote cancer initiation and progression. Furthermore, microbiome–epigenetic interactions control the innate and adaptive immunity causing exacerbation of cancer progression and therapeutic resistance. This review discusses epigenetic mechanisms with more focus on miRNAs and their interaction with the microbiome. The potential use of epigenetic alterations and microbiota as specific biomarkers to aid in the early detection and/or development of therapeutic targets is explored. The advancement of combinatorial therapies to prolong overall patient survival or possible eradication of MM especially if it is detected early is discussed.en© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).MesotheliomaEpigeneticsMicroRNAMicrobiomeImmune modulationAlternative splicingAsbestosTherapeutic targetsMalignant mesotheliomasLow- and middle-income countries (LMICs)Article