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Recent evidence has increasingly underscored the significance of epigenetic reprogramming as a principal mechanism through which Mtb modifies host cellular functions without altering the fundamental DNA sequence. This review gives a full picture of how Mtb secretory proteins work as nucleomodulins to directly target host chromatin and control gene expression. Mtb uses special secretion systems, such as the ESX (Type VII) and SecA2 pathways, to enable effector proteins to enter host cells. Some of these proteins move to the nucleus and interact with machinery that is linked to chromatin. These nucleomodulins facilitate various epigenetic modifications, encompassing non-canonical histone methylation, DNA methylation, and the modulation of histone acetylation, resulting in extensive transcriptional reprogramming of immune-related genes. These changes make important host defence mechanisms less effective, such as macrophage activation, antigen presentation, cytokine production, and antimicrobial responses. This helps bacteria survive and avoid the immune system. Epigenetic remodeling also affects the polarization and metabolic states of macrophages, which further affect the progression of disease. The reversible characteristics of epigenetic modifications offer a significant prospect for host-targeted therapeutic strategies. Targeting enzymes such as histone deacetylases and DNA methyltransferases has shown potential in restoring immune function and enhancing bacterial clearance, particularly when used in combination with conventional anti-tubercular therapies. Even with these improvements, there are still big problems with fully understanding the functional diversity of Mtb secretory proteins and turning these discoveries into useful medical tools. In general, understanding how Mtb-secreted nucleomodulins and host epigenetic regulation interact is important for understanding how tuberculosis works and finding new ways to treat it.<\/jats:p>","DOI":"10.3390\/antibiotics15060557","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:37:26Z","timestamp":1780454246000},"page":"557","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Reprogramming by Mycobacterium tuberculosis Secretory Proteins: Implications for Pathogenesis and Therapy"],"prefix":"10.3390","volume":"15","author":[{"given":"Krishna","family":"RV","sequence":"first","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nafsiya","family":"Asif","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akash N.","family":"Sethunath","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak T.","family":"Thekkumkara","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devanandana","family":"Binu","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gowri","family":"Krishna","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarsha A.","family":"Sureshkumar","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun M.","family":"Menon","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shwetha Susan","family":"Thomas","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuniyil","family":"Abhinand","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Kollam 690525, Kerala, 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