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This suggests an unidentified transcription regulator between CTSL and CUX1, and CTSL\u2010mediated cleavage of this regulator could transcribe CUX1, inducing senescence. Here, in search of this transcriptional regulator, we discovered that Notch1 is a substrate of CTSL, and CTSL can proteolytically activate Notch1 in a ligand\u2010independent fashion, liberating NICD. NICD, after complexing with RBPJ in the nuclei, induces CUX1\/p16\n                    <jats:sup>INK4a<\/jats:sup>\n                    \u2010dependent senescence. Consistently, an upregulation of both CTSL and NICD, along with elevated cellular senescence in the plaques isolated from patients with atherosclerosis, was observed. In addition, we showed that endothelial deletion of CUX1 in the\n                    <jats:italic>atherosclerosis\u2010prone<\/jats:italic>\n                    ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice blocks high\u2010fat diet\u2010induced senescence throughout the entire plaques, and these ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice exhibit similar phenotypes as the atherosclerosis\u2010prone models with CTSL and Notch1\/RBPJ inactivation including attenuated atherosclerotic lesion, intact and well\u2010organized elastin fibers, and reduced macrophage content of plaque. This further supports our findings that both CTSL and Notch1\/RBPJ are upstream regulators of CUX1, regulating senescence. Thus, while our studies identify a non\u2010canonical Notch1 pathway that can be activated by CTSL in a ligand\u2010independent fashion to induce senescence, our findings also reveal a role of senescence in the development of atherosclerosis. This provides new insight into developing drugs aimed to target cellular senescence for atherosclerosis.\n                  <\/jats:p>","DOI":"10.1111\/acel.70563","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T06:20:57Z","timestamp":1780035657000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ligand\u2010Independent Activation of Notch1 by Cathepsin L Induces\n                    <scp>CUX1<\/scp>\n                    \/\n                    <scp>\n                      p16\n                      <sup>INK4a<\/sup>\n                    <\/scp>\n                    \u2010Dependent Endothelial Senescence Associated With Atherosclerosis"],"prefix":"10.1111","volume":"25","author":[{"given":"Yuwei","family":"Wu","sequence":"first","affiliation":[{"name":"Aging Institute University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Cardiology, Third Xiangya Hospital Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Lu","sequence":"additional","affiliation":[{"name":"Aging Institute University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoyang","family":"Yan","sequence":"additional","affiliation":[{"name":"Aging Institute University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zewen","family":"Du","sequence":"additional","affiliation":[{"name":"Aging Institute University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danli","family":"Jiang","sequence":"additional","affiliation":[{"name":"Aging Institute University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1708-2869","authenticated-orcid":false,"given":"Ting","family":"Wu","sequence":"additional","affiliation":[{"name":"Aging Institute University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Cardiology, Third Xiangya Hospital Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qichao","family":"Wu","sequence":"additional","affiliation":[{"name":"Aging Institute University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Aging Institute University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johny","family":"Ebin","sequence":"additional","affiliation":[{"name":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Sun","sequence":"additional","affiliation":[{"name":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Partha","family":"Dutta","sequence":"additional","affiliation":[{"name":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay Xiaojun","family":"Tan","sequence":"additional","affiliation":[{"name":"Aging Institute University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Cell Biology University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3741-6512","authenticated-orcid":false,"given":"Jonathan K.","family":"Alder","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Dorothy P. and Richard P. 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