Mycobacterial and host non-coding RNAs in tuberculosis: immunoregulatroy functions, adaptation strategies, and biomarker potential

Tuberculosis (TB), caused by members of the Mycobacterium tuberculosis complex (MTBC), remains a major global health challenge, with over 10 million new cases and more than 1 million deaths reported annually. Ten distinct human-adapted MTBC lineages circulate worldwide, contributing to the pathogen’s remarkable evolutionary success. Non-coding RNAs (ncRNAs) have emerged as key molecular regulators that can influence pathogen survival, immune responses, and disease progression. For the pathogen, ncRNAs regulate virulence, stress adaptation, metabolism, dormancy, persistence, and drug tolerance, thereby enabling it to survive hostile host environments. In the host, ncRNAs modulate critical immune processes, including macrophage activation, cytokine production, inflammation, cell death pathways, and antigen presentation. Advances in next-generation sequencing and transcriptomics have accelerated the discovery of ncRNA-mediated regulatory networks involved in TB pathogenesis and host–pathogen interactions. Experimental studies have demonstrated the immunoregulatory roles of host ncRNAs in shaping protective and pathological responses to M. tuberculosis infection, while mycobacterial ncRNAs have been linked to adaptation, virulence, and antibiotic resistance. In this review, we provide an integrated, cross-kingdom overview of host-derived ncRNAs, including miRNAs, lncRNAs, and circRNAs, as well as M. tuberculosis -encoded sRNAs. We highlight their roles in immune regulation, TB pathogenesis, and pathogen adaptation, as well as their potential as diagnostic and prognostic biomarkers and therapeutic targets. We summarize current knowledge of their biogenesis and expression patterns during M. tuberculosis infection and examine the regulatory mechanisms through which ncRNAs modulate host immune responses and bacterial adaptation strategies, ultimately influencing TB disease outcomes. Finally, we discuss the translational relevance of ncRNAs in TB diagnosis, prognosis, and treatment, highlighting key opportunities and challenges to advance their clinical application and improve TB control.