Background <p>Clinical and epidemiological studies suggest a notably higher incidence of atherosclerosis (AS) in systemic sclerosis (SSc) patients, yet their shared molecular mechanisms remain unclear. Therefore, this research was designed to investigate the shared pathogenic mechanisms underlying both SSc and AS.</p> Methods <p>SSc and AS datasets were acquired from the Gene Expression Omnibus (GEO) database to identify common differentially expressed genes (DEGs). Subsequently, enrichment analyses, protein–protein interaction (PPI) network analysis, coexpression analysis, and TF-mRNA-miRNA regulatory network construction were performed on these common DEGs. Finally, the hub genes were validated using external datasets. Additionally, immune cell infiltration in both SSc and AS was analyzed via the CIBERSORT algorithm, and the relationships between hub genes and immune cell infiltration were assessed.</p> Results <p>A total of 104 DEGs were identified, with 99 upregulated and 5 downregulated genes. Functional enrichment analysis indicated that the pathogenic mechanisms of these genes are related to immune processes. Through comprehensive bioinformatics analysis, three hub genes (ITGB2, CD163, and CCR5) were identified. Comparative analysis revealed marked upregulation of these genes in pathological specimens relative to controls, highlighting their diagnostic biomarker potential. Furthermore, immune profiling demonstrated macrophage and T lymphocyte predominance in disease microenvironments, implicating these immune populations in SSc and AS pathogenesis.</p> Conclusion <p>Our study revealed common biomarkers and immune-related pathways that may contribute to the pathogenesis of both SSc and AS. These findings suggest potential immunological mechanisms underlying the development of AS in patients with SSc, providing new insights into the pathological links between these two diseases.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p>• <i>ITGB2, CD163, and CCR5 may be new diagnostic biomarkers for SSc and AS.</i></p> <p>• <i>Macrophages and T lymphocytes as key mediators in SSc and AS pathogenesis.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>