Background: The differential diagnosis of tuberculosis (TB) and lung cancer (LC) is often challenging due to similar clinicopathological presentations when bacterial shedding is negative, which can lead to delays in treatment. In this study, we tested the potential of plasma-circulating microRNAs (miRNAs) for the early and differential diagnosis of TB and LC. Methods: We conducted a two-phase study: profiling 188 miRNAs in pooled plasma samples and validating 14 selected miRNAs in individual plasma samples from 68 LC patients, 38 pulmonary TB patients, and 41 healthy controls. Results: Twelve miRNAs were significantly elevated in LC patients compared to controls and TB patients, while two miRNAs were significantly elevated in TB patients compared to controls. ROC analysis demonstrated that miR-130b-3p, miR-1-3p, miR-423-5p, and miR-200a-3p had good discriminatory ability to distinguish LC patients (including those with stage I tumours) from healthy individuals and miR-130b-3p, miR-423-5p, miR-15b-5p, and miR-18b-5p effectively distinguished LC patients (including those with stage I tumours) from TB patients. Additionally, miR-18b-5p showed good discriminatory ability between SCLC and NSCLC patients. Conclusions: Circulating miRNAs hold strong potential for the early detection of LC and for distinguishing LC from TB.

Background/Objectives: The differential diagnosis of tuberculosis (TB) and lung cancer (LC) is often challenging due to similar clinicopathological presentations when bacterial shedding is negative, which can lead to delays in treatment. In this study, we tested the potential of plasma-circulating microRNAs (miRNAs) for the early and differential diagnosis of TB and LC. Methods: We conducted a two-phase study: profiling 188 miRNAs in pooled plasma samples and validating 14 selected miRNAs in individual plasma samples from 68 LC patients, 38 pulmonary TB patients, and 41 healthy controls. Results: Twelve miRNAs were significantly elevated in LC patients compared to controls and TB patients, while two miRNAs were significantly elevated in TB patients compared to controls. ROC analysis demonstrated that miR-130b-3p, miR-1-3p, miR-423-5p, and miR-200a-3p had good discriminatory ability to distinguish LC patients (including those with stage I tumours) from healthy individuals and miR-130b-3p, miR-423-5p, miR-15b-5p, and miR-18b-5p effectively distinguished LC patients (including those with stage I tumours) from TB patients. Additionally, miR-18b-5p showed good discriminatory ability between SCLC and NSCLC patients. Conclusions: Circulating miRNAs hold strong potential for the early detection of LC and for distinguishing LC from TB.

The differential diagnosis of lung cancer and pulmonary tuberculosis (PTB) remains challenging because the diseases share clinical manifestations and radiological features, particularly in regions with a high tuberculosis burden. This narrative review evaluates circulating microRNAs (miRNAs), primarily measured in serum, plasma and extracellular-vesicle-enriched fractions, as potential adjunctive biomarkers for this differential diagnosis. The literature search was updated through 3 October 2026. Evidence was synthesized by comparator group, biological matrix, analytical methodology and validation design, distinguishing direct lung cancer–PTB comparisons from disease–control studies and prognostic or monitoring investigations. Numerous miRNAs have been associated with either disease, but shared candidates and opposite expression directions across separate studies do not establish differential diagnostic accuracy. Findings vary with patient selection, sample processing, detection platforms, normalization and reference standards. Direct blood-based comparisons remain limited and report variable discrimination. A plasma panel comprising miR-342-3p, miR-199a-3p and miR-199b-3p differentiated PTB from lung cancer with areas under the curve of 0.911 in training and 0.886 in internal split-sample validation; validation sensitivity and specificity were 87.9% and 75.9%, respectively. Its case–control design, incomplete microbiological confirmation and absence of concomitant lung cancer–PTB assessment limit clinical interpretation. Additional pleural-fluid findings concern a separate matrix and cannot be extrapolated to blood testing. Prognostic and treatment-associated findings remain exploratory and do not establish treatment-guiding or validated monitoring utility. Circulating miRNAs should therefore be considered potential adjuncts to clinical assessment, imaging, microbiological testing and histopathology. Clinical translation requires standardized assays, independent prospective validation in clinically relevant populations, and demonstration of incremental value and clinical utility within existing diagnostic pathways. Future studies should prespecify intended use, assay procedures and diagnostic thresholds, include patients with coexisting disease, and evaluate whether testing improves clinical decisions without replacing established microbiological or tissue confirmation methods.