The Evolving Landscape of Systemic Sclerosis Pathogenesis: From Foundational Mechanisms to Organ-Specific Modifiers

Systemic sclerosis (SSc) is a multifaceted autoimmune disease in which the complex interplay of genetic predisposition and environmental factors triggers aberrant immune responses, ultimately leading to vasculopathy and fibrosis. This review offers a comprehensive overview of current perspectives on SSc pathogenesis, integrating classical concepts with recent breakthroughs enabled by advanced analytical techniques. We delve into the foundational trans-organ pathophysiology of SSc, encompassing epigenetic dysregulation, chronic inflammation, vascular injury, vasculopathy, and fibrosis. Furthermore, we explore the organ-specific modifiers that contribute to the heterogeneity of SSc manifestations across different organ systems, including the skin, gastrointestinal tract, lungs, and heart. Recent studies employing single-cell transcriptomics, spatial proteomics, and epigenomic profiling are highlighted, demonstrating how these technologies are revolutionizing our understanding of SSc cellular and molecular pathology. This evolving landscape of SSc pathogenesis research is critical for identifying novel therapeutic targets and advancing personalized medicine approaches for SSc patients.