Host-directed therapy for tuberculosis: Repurposed drugs toward global tuberculosis elimination

Despite the World Health Organization End TB Strategy, tuberculosis (TB) remains the world's leading infectious cause of death. Conventional antimicrobial therapies are hindered by prolonged treatment durations, poor patient adherence, and drug toxicity. Host-directed therapies (HDTs) have therefore emerged as a promising adjunctive strategy aimed to enhance bacterial clearance, reduce immunopathology, and improve functional recovery. This review synthesizes the mechanistic and clinical evidence supporting repurposed, affordable agents for use in high TB-burden, resource-limited settings. We categorize the HDT candidates by their targeted host pathways, including autophagy (metformin, vitamin D, all-trans retinoic acid), inflammatory signaling (nonsteroidal anti-inflammatory drugs), immunomodulation (corticosteroids), matrix metalloproteinase inhibition (doxycycline), lipid metabolism (statins, PSCK9 inhibitors), tumor necrosis factor-⍺ inhibitors (adalimumab, infliximab), redox homeostasis (glutathione, N-acetylcysteine), and immunothrombosis. We further highlight their relevance across pulmonary TB and extrapulmonary TB, their potential benefits in TB-associated comorbidities such as HIV and diabetes mellitus, and key findings from randomized controlled trials. However, transitioning these agents into standard clinical practice requires large-scale, stratified Phase III trials. Integrating HDTs alongside conventional antimicrobial therapy will be essential to accelerate the progress toward global TB elimination.