A mitochondria-related 9-gene induced sputum signature for severe asthma: an integrative transcriptomic analysis with external validation

OBJECTIVE: Severe asthma is biologically heterogeneous, and airway-derived biomarkers for disease stratification remain limited. We aimed to identify a mitochondria-related induced sputum transcriptomic signature associated with severe asthma. METHODS: Two public induced sputum microarray datasets were analyzed: GSE76262 as the discovery cohort and GSE147880 as the external validation cohort. Mitochondrial activity was quantified by single-sample gene set enrichment analysis using the MitoCarta 3.0 gene set. In differential expression analysis, severe asthma was compared against a combined reference group of non-severe asthma and healthy controls (i.e., non-severe asthma and healthy controls combined into a single reference group). Weighted gene co-expression network analysis, and LASSO logistic regression were subsequently used to derive a mitochondria-related gene signature. External validation, multivariable logistic regression, immune infiltration analysis, and nomogram construction were further performed. RESULTS: Severe asthma showed broad transcriptomic remodeling, including 2,000 differentially expressed genes, of which 196 were mitochondria-related. Mito Score was significantly reduced in severe asthma and discriminated severe disease with an area under the curve (AUC) of 0.791. A key co-expression module associated with Mito Score yielded candidate genes enriched in oxidative phosphorylation, thermogenesis, cellular respiration, and reactive oxygen species-related pathways. LASSO identified a 9-gene signature consisting of CLC, IL18R1, SLC7A11, MARCH1, RBMS2, MAN2B2, SMOX, TTC15, and CD4. The signature showed good discrimination in the discovery cohort (AUC 0.892) and retained performance in the external validation cohort (AUC 0.758). Risk Score remained independently associated with severe asthma after adjustment for age and sex. CONCLUSION: Induced sputum transcriptomics identified a reproducible mitochondria-related 9-gene signature associated with severe asthma, supporting mitochondrial dysfunction as a clinically relevant airway feature and a candidate biomarker framework for disease stratification.