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Monocytes play key roles in host defense against malaria through cytokine production and phagocytosis; however, they are also implicated in pathogenesis through excessive proinflammatory cytokine production. Understanding the underlying molecular mechanisms that contribute to inflammatory cytokine production in <jats:italic>P. falciparum<\/jats:italic>-exposed monocytes is key towards developing better treatments. Here, we provide molecular evidence that histone 3 lysine 4 (H3K4) methylation is key for inflammatory cytokine production in <jats:italic>P. falciparum<\/jats:italic>-exposed monocytes. In an established in vitro system that mimics blood stage infection, elevated proinflammatory TNF and IL-6 cytokine production is correlated with increased mono- and tri-methylated H3K4 levels. Significantly, we demonstrate through utilizing a pharmacological inhibitor of H3K4 methylation that TNF and IL-6 expression can be suppressed in <jats:italic>P. falciparum<\/jats:italic>-exposed monocytes. This elucidated epigenetic regulatory mechanism, controlling inflammatory cytokine production, potentially provides new therapeutic options for future malaria treatment.<\/jats:p>","DOI":"10.1038\/s41598-024-53519-w","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T13:03:17Z","timestamp":1707138197000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Epigenetic and transcriptional regulation of cytokine production by Plasmodium falciparum-exposed monocytes"],"prefix":"10.1038","volume":"14","author":[{"given":"David V. 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