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Emerging evidence indicates that epigenetic regulation is fundamental to host\u2013pathogen interactions, influencing transcriptional programmes associated with virulence, immune evasion, stress adaptation, and phenotypic plasticity. In organisms such as bacteria, parasites, and intracellular pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum, chromatin-associated regulators and DNA-modifying enzymes have been identified as dosage-sensitive determinants of infection outcomes. Traditional strategies focus primarily on occupancy-driven enzymatic inhibition. In contrast, targeted protein degradation (TPD) introduces an event-driven pharmacological paradigm in which transient ligand engagement triggers sustained depletion of regulatory proteins. Platforms such as proteolysis-targeting chimeras (PROTACs) and BacPROTACs exemplify the ability to exploit host and pathogen proteolytic systems, thereby expanding the druggable proteome beyond conventional small-molecule targets. This review examines the relationship between epigenetic regulation and pathogen survival, highlights recent advances in degradation technologies, and discusses conceptual and translational challenges in implementing TPD in antimicrobial and antiparasitic drug discovery.<\/jats:p>","DOI":"10.3390\/ijms27093977","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:01:18Z","timestamp":1777474878000},"page":"3977","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Epigenetic Regulation to Protein Degradation: Emerging Strategies for Anti-Infective Drug Discovery"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8666-008X","authenticated-orcid":false,"given":"Andressa Francielli","family":"Bonjorno","sequence":"first","affiliation":[{"name":"S\u00e3o Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara 14800-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9323-4735","authenticated-orcid":false,"given":"Diogo","family":"Boreski","sequence":"additional","affiliation":[{"name":"S\u00e3o Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara 14800-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2643-810X","authenticated-orcid":false,"given":"Ana Lu\u00edsa","family":"Rodriguez Gini","sequence":"additional","affiliation":[{"name":"S\u00e3o Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara 14800-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3019-5393","authenticated-orcid":false,"given":"Pamela","family":"Souza Tada da Cunha","sequence":"additional","affiliation":[{"name":"S\u00e3o Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara 14800-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3696-1085","authenticated-orcid":false,"given":"Jhonnathan Alves","family":"Moura","sequence":"additional","affiliation":[{"name":"S\u00e3o Paulo State University (UNESP), Institute of Chemistry, Araraquara 14800-060, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4141-0455","authenticated-orcid":false,"given":"Chung Man","family":"Chin","sequence":"additional","affiliation":[{"name":"S\u00e3o Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara 14800-903, Brazil"},{"name":"Advanced Research Center in Medicine (CEPAM), School of Medicine, Union of the Colleges of the Great Lakes (UNILAGO), S\u00e3o Jos\u00e9 do Rio Preto 15030-070, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2540-6395","authenticated-orcid":false,"given":"Cau\u00ea","family":"Benito Scarim","sequence":"additional","affiliation":[{"name":"S\u00e3o Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara 14800-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2460-2829","authenticated-orcid":false,"given":"Jean Leandro","family":"Dos Santos","sequence":"additional","affiliation":[{"name":"S\u00e3o Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara 14800-903, Brazil"},{"name":"S\u00e3o Paulo State University (UNESP), Institute of Chemistry, Araraquara 14800-060, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1038\/s41467-021-24580-0","article-title":"Epigenetic memories and the evolution of infectious diseases","volume":"12","author":"McLeod","year":"2021","journal-title":"Nat. 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