HMGB1 and sRAGE levels were elevated in SSc patients and mouse models. Platelets-derived particles expressed HMGB1, which promoted autophagy of neutrophils, enhanced proteolytic enzyme activity, and generated neutrophils extracellular traps. HMGB1 promotes the expression of α2AP in fibroblasts and contributes to tissue fibrosis. HMGB1 may be an independent risk factor for SSC-ILD or a new biomarker for SSc patients. This evidence concerns the gene SERPINF2 and interstitial lung disease.