Background: Cellular senescence is a critical contributor to the pathogenesis of systemic sclerosis-associated interstitial lung disease (SSc-ILD). However, the roles of aging-related genes in disease onset and progression remain unclear. We aimed to identify the clinical features and senescence-associated genetic signatures of SSc-ILD and validate the role of insulin-like growth factor-binding protein 2 (IGFBP2) in basal cell senescence and fibrotic progression. Methods: The cohort comprised 106 patients with SSc hospitalized between January 2020 and December 2023 who were divided into SSc-ILD ( n = 73) and SSc-NILD ( n = 33) groups. Baseline clinical data were compared, and independent risk factors were identified using stepwise multivariate logistic regression analysis to develop a clinical nomogram. Gene expression datasets were downloaded from the Gene Expression Omnibus (GSE231693 as the training set; GSE48149, GSE76808, and GSE81292 as the validation sets). Aging-related genes were retrieved from CellAge and GeneCard databases. Differentially expressed genes (DEGs) were identified and subjected to a functional enrichment analysis. Weighted gene co-expression network analysis combined with the least absolute shrinkage and selection operator, random forest, and support vector machine–recursive feature elimination algorithms identified hub genes. A senescence-related gene diagnostic nomogram was developed, and its receiver operating characteristics were validated. The biomarkers were experimentally validated in a bleomycin-induced SSc-ILD mouse model using immunofluorescence, quantitative polymerase chain reaction, and western blotting. Single-cell RNA sequencing (GSE159354) was used to assess IGFBP2 expression across lung cell populations. IGFBP2 was selectively knocked down in basal cells using AAV6-IGFBP2 delivered shRNA to evaluate its fibrotic role. Results: The independent risk factors for SSc-ILD included age ≥50 years, diffuse cutaneous involvement, hyperlipidemia, dyspnea, and anti-Scl-70 positivity. Among the 1061 aging-related genes, 68 were identified as aging-related DEGs, of which four were identified as hub genes (IGFBP2, ABCB1, CXCR2, and MEOX1). The gene-based nomogram demonstrated a strong diagnostic performance (area under the curve = 0.92). IGFBP2 is upregulated in fibrotic lungs and localized to basal and ciliated cells, whereas its targeted knockdown attenuates pulmonary fibrosis. Conclusion: Our results indicate that IGFBP2 is a key senescence-associated biomarker of SSc-ILD. The integrative approach used in this study provides a robust framework for the discovery of therapeutic targets.
Li et al. (Thu,) studied this question.