Comparative molecular analysis of histopathologic subtypes reveals shared epithelial remodeling yet distinct fibroblast programs in scleroderma lung disease

Single-nucleus RNA-seq and spatial mapping of explanted lungs show shared epithelial remodeling in SSc-NSIP and SSc-UIP, including alveolar type 1 loss and pathologic AT2 programs.

• Why it matters: ILD in systemic sclerosis can progress to PPF, but the cellular programs behind NSIP versus UIP patterns are unclear, limiting subtype-specific understanding.
• What they did: The study profiled 120,254 nuclei from 6 SSc-NSIP, 6 SSc-UIP, 6 IPF, and 12 control donors using single-nucleus RNA sequencing and spatial transcriptomics, validated by immunohistochemistry and western blot.
• The result: Fibroblast states differed by subtype—CTHRC1 profibrotic fibroblasts neighbored aberrant basaloid cells in both SSc groups, while TGF-{beta} signaling was amplified in UIP, distinguishing SSc-NSIP from SSc-UIP and IPF.

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