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Medial arterial calcification (MAC) is common in LEAD patients and contributes to disease\u2010related mortality. However, therapeutic strategies targeting femoral MAC are lacking, and its underlying mechanisms remain unclear. This study aimed to identify molecular drivers of femoral MAC in LEAD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods &amp; Results<\/jats:title>\n                    <jats:p>\n                      Calcium deposits and pro\u2010calcifying markers were analyzed in human patient samples using von Kossa staining, immunofluorescence, and gene expression analysis. Femorals showed significantly more calcification and pro\u2010calcifying gene expression than carotids. Given MAC abundance in LEAD, we assessed medial calcification in\n                      <jats:italic>Apoe\u2212\/\u2212<\/jats:italic>\n                      mice fed a WD for 4\/21\u2009weeks. Digital PCR revealed upregulation of\n                      <jats:italic>Ddr1<\/jats:italic>\n                      and\n                      <jats:italic>Bmp2<\/jats:italic>\n                      in femoral versus carotid arteries after 21\u2009weeks of WD. DDR1 expression positively correlated with calcification in human femoral samples. In\u00a0vitro experiments with mouse femoral vs. carotid vascular smooth muscle cells (VSMCs) confirmed a significantly higher prevalence of calcifying proteins (DDR1, BMP2, and RUNX2) in femoral VSMCs. Additionally, calcification analyses in murine and human VSMCs showed that DDR1 inhibition reduced, while DDR1 activation increased, calcium deposition. Transcriptomic analysis revealed elevated NF\u2010\u03baB expression in human femoral arteries, matching data in femoral VSMCs. DDR1 stimulation activated NF\u2010\u03baB, and its inhibition blocked DDR1\u2010induced calcification.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identifies DDR1 as a key driver of calcification in LEAD, operating through NF\u2010\u03baB activation and the expression of calcifying proteins. Targeting DDR1 may offer a novel therapeutic approach to prevent MAC in LEAD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70146","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T09:33:09Z","timestamp":1765877589000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>DDR1<\/scp>\n                    Regulates Femoral Arterial Calcification in Lower\u2010Extremity Artery Disease Through\n                    <scp>NF<\/scp>\n                    \u2010Kappa B Activation"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3825-4121","authenticated-orcid":false,"given":"Manovriti","family":"Thakur","sequence":"first","affiliation":[{"name":"Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital University of Bern  Bern Switzerland"},{"name":"Department for BioMedical Research (DBMR) University 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