Long Non-Coding RNAs in Tuberculosis: From Pathogenesis to Precision Therapeutics

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), is among the most prominent causes of global mortality, with the latest records pointing towards approximately 1.3 million deaths in 2023. Despite the worldwide use of the Bacillus Calmette-Guérin (BCG) vaccine and standard anti-TB drugs, the appearance of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains is on the rise. This trend legitimately demands a shift in our focus toward the host-directed interventions. Recently, long non-coding RNAs (lncRNAs) have emerged as regulators at the interface between the immune and metabolic systems during Mtb infection. They function as molecular regulators that coordinate inflammatory signalling and cellular energy metabolism. This review attempted to provide critical insights into how lncRNAs are regulated during a TB infection. Circulating lncRNAs show clear diagnostic potential, with some signatures outperforming conventional tests in discovery-phase cohorts; however, we also discuss significant implementation barriers in high-burden countries, including ultra-cold-chain logistics for RNA-based platforms. We have highlighted the need for translational development to move from cell lines to primary human cells and clinical cohorts. Unlike prior reviews that majorly catalogue TB-associated lncRNAs, this literature-based study delineates an evidence-level stratification framework and a five-tier translational roadmap to guide clinical development of lncRNA-targeted host-directed therapies.