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 com-prehensive 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 epige-netic dysregulation, chronic inflammation, vascular injury, vasculopathy, and fibrosis. Furthermore, we explore the organ-specific modifiers that contribute to the heteroge-neity of SSc manifestations across different organ systems, including the skin, gastro-intestinal 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 pa-thology. This evolving landscape of SSc pathogenesis research is critical for identifying novel therapeutic targets and advancing personalized medicine approaches for SSc pa-tients.