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TB, caused by the bacterial species Mycobacterium tuberculosis, is highly frequent in people living with HIV. The continuing epidemics of both chronic infections and the emergence of antimicrobial resistance, as well as the lack of effective diagnostic tools and drug\u2013drug interactions, pose major challenges in the fight against these pathogens. Developing a wide range of host-directed therapies may improve treatment outcomes, helping alleviate the morbidity and mortality associated with both infections. In this review, we discuss the identification and development of new host-directed strategies based on protease inhibitors and their clinical relevance as adjunctive treatment. In the context of therapeutic agents with novel mechanisms, selective protease inhibitors, including saquinavir (SQV) and cystatins (CstC and CstF), are valuable targets that may provide effective therapeutic solutions for controlling Mtb and HIV coinfection.<\/jats:p>","DOI":"10.3390\/microorganisms13051040","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T05:10:32Z","timestamp":1746076232000},"page":"1040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Host-Directed Therapies Based on Protease Inhibitors to Control Mycobacterium tuberculosis and HIV Coinfection"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3997-9618","authenticated-orcid":false,"given":"Manoj","family":"Mandal","sequence":"first","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-1516","authenticated-orcid":false,"given":"David","family":"Pires","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"},{"name":"Center for Interdisciplinary Research in Health, Cat\u00f3lica Medical School, Universidade Cat\u00f3lica Portuguesa, Estrada Oct\u00e1vio Pato, 2635-631 Rio de Mouro, Portugal"}]},{"given":"Jos\u00e9 Miguel","family":"Azevedo-Pereira","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5934-0198","authenticated-orcid":false,"given":"Elsa","family":"Anes","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025, January 14). 2024 Global Tuberculosis Report. Available online: https:\/\/www.who.int\/teams\/global-tuberculosis-programme\/tb-reports\/global-tuberculosis-report-2024."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Houben, R.M.G.J., and Dodd, P.J. (2016). The Global Burden of Latent Tuberculosis Infection: A Re-Estimation Using Mathematical Modelling. 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