{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:44:02Z","timestamp":1787028242640,"version":"build-2736575974"},"reference-count":201,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Systemic sclerosis (SSc) is a rare, complex autoimmune disease characterized by fibrosis of the skin and internal organs. While its pathogenesis is not fully understood, chromosomal instability and telomere attrition have emerged as significant areas of investigation. Methods: This review provides a historical narrative perspective and synthesizes current findings on the role of these genomic anomalies in SSc pathogenesis. We synthesized findings from foundational and recent research articles investigating genotoxic factors, chromosomal aberrations, and telomere biology in SSc. Results: There is a strong historical basis for chromosomal instability in SSc, manifesting as micronuclei, translocations, and breaks. This instability is driven by clastogenic factors and oxidative stress. SSc-specific autoantibodies are implicated; anti-centromere antibodies correlate with aneuploidy and micronuclei, while anti-topoisomerase I may inhibit DNA repair. SSc is also characterized by significant telomere attrition, first reported in 1996 and now confirmed by additional genetic studies. This telomere loss is associated with reduced telomerase activity and the presence of autoantibodies against telomere-associated proteins, including shelterin components. Conclusions: We conclude that inflammation, telomere attrition, and chromosomal instability are linked in a self-perpetuating cycle that drives SSc pathogenesis. We propose that an initial inflammatory stimulus leads to reactive oxygen species production, causing telomere damage and attrition. Critically short telomeres trigger faulty DNA repair mechanisms, such as breakage\u2013fusion\u2013bridge cycles, resulting in chromosomal instability. This genomic damage, in turn, acts as a danger signal, further activating inflammatory pathways and creating a feedback loop that perpetuates fibrosis.<\/jats:p>","DOI":"10.3390\/genes16121466","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T10:35:51Z","timestamp":1765190151000},"page":"1466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Chromosomal Instability and Telomere Attrition in Systemic Sclerosis: A Historical Perspective"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9060-0581","authenticated-orcid":false,"given":"Carol M.","family":"Artlett","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University, Philadelphia, PA 19129, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s12016-018-8718-8","article-title":"Antinuclear Antibodies in Systemic Sclerosis: An Update","volume":"58","author":"Stochmal","year":"2020","journal-title":"Clin. 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