Epigenetic reprogramming in tuberculosis: mechanisms of immune evasion and host-directed therapies

Mycobacterium tuberculosis (Mtb) evades host immunity by actively reprogramming host gene expression, which allows the pathogen to persist within immune cells. Recent high-throughput sequencing and epigenomic studies have shown that Mtb reshapes the host epigenetic landscape by altering DNA methylation, histone modifications (including acetylation and methylation), and non-coding RNA networks. These modifications impact immune transcriptional programs and create an intracellular environment that favors bacterial survival. Importantly, these reversible epigenetic signatures offer promising pharmacological targets. This review systematically explores the immunological consequences of host epigenetic regulation during Mtb infection, evaluates the mechanisms of trained immunity, and highlights the therapeutic potential of pharmacological epigenetic modulators, such as inhibitors of histone deacetylases, DNA methyltransferases, and miRNA modulators. Furthermore, it discusses the development of emerging druggable targets, including novel epigenetic modifiers and immunometabolic hubs, while emphasizing the potential synergy of combining these epigenetic host-directed therapies with conventional antibiotics for treating tuberculosis.