Single‐Cell Profiling Reveals Divergent Mechanisms of Fibrosis in Localized Scleroderma and Systemic Sclerosis

Objectives Localized scleroderma (LoS) and systemic sclerosis (SSc) are both fibrotic diseases, but LoS is limited to the skin, whereas SSc involves systemic organ fibrosis. This study aimed to elucidate the mechanisms underlying these differences. Methods Skin biopsies from 3 healthy controls, 3 patients with LoS, and 3 patients with SSc underwent immunofluorescence and single‐cell RNA sequencing (scRNA‐seq). Key molecular functions were validated using in vitro assays and murine models. Results Immunofluorescence revealed a high prevalence of tertiary lymphoid structures (TLS) in LoS lesions (65.7%) compared to SSc (14.3%, p = 0.0013). scRNA‐seq identified T follicular helper (Tfh) cells enriched within TLS in LoS. Tfh cells likely promote B cell recruitment via the CXCL13/CXCR5 axis, and integrin α4 may support Tfh cell retention, contributing to TLS stability. These organized immune aggregates, together with elevated TGF‐β expression, may drive localized fibroblast activation and skin fibrosis in LoS. In contrast, SSc lesions contained fibroblasts with high CREB3L1 expression. CREB3L1 overexpression increased type I collagen, fibronectin 1, and periostin levels in fibroblasts, while knockdown reduced them. In a SSc mouse model, CREB3L1 upregulation worsened skin and lung fibrosis, whereas knockdown alleviated it. Conclusion These findings suggest that LoS fibrosis is driven by TLS‐mediated local immune activation, whereas the systemic activation of CREB3L1‐expressing fibroblasts plays an important role in SSc fibrosis. Targeting local inflammation may benefits LoS, while targeting CREB3L1 offers a promising antifibrotic strategy in SSc.