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Introduction Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). Current clinical and serum biomarkers such as KL-6 and CRP are useful but lack sensitivity and specificity in predicting progression. Identifying immune cell-derived molecular predictors could enable earlier intervention and refine patient stratification.Material and Methods We performed integrative transcriptomic profiling of peripheral blood from patients with progressive SSc-ILD (n=39 bulk RNA-seq, n=13 single-cell RNA-seq (scRNA-seq)), stable SSc-ILD (n=43 bulk; n=14 single-cell), and healthy controls (n=6 single-cell). Serum biomarkers were quantified in parallel. Single-cell pseudobulk expression per patient was compared using non-parametric tests with multiple-comparison correction.Results LOXHD1 was significantly elevated in CD14+ monocytes from progressive SSc-ILD with enrichment of inflammatory signaling pathways (figure 1A). RHOB was upregulated in both CD14+ and CD16+ monocytes across single-cell and bulk RNA datasets (figure 1B, 1C). Consistent with known predictors, male sex, elevated KL-6, and higher CRP were also associated with progression. Additional transcriptomic changes included downregulation of ATXN2L in progressive (single-cell) and upregulation of S100A2, CHI3L1, and MMP9 in bulk RNA-seq, consistent with prior microarray studies. These findings confirm known biology while highlighting new, monocyte-specific progression markers.Conclusions Our integrative analysis identifies LOXHD1 and RHOB as reproducible blood-based biomarkers of progressive SSc-ILD, complementing established clinical and serum predictors. By anchoring risk stratification in immune cell transcriptomics, these results support incorporating monocyte gene profiling into future monitoring and clinical trial enrichment. Multicenter validation is now warranted to test their utility for precision care in SSc-ILD.