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However, the upstream signaling pathways that converge on the transcriptional machinery to drive VSMC degeneration remain elusive. Here, we integrated single-nucleus (sn) multi-omics, chromatin immunoprecipitation (ChIP)-seq, and wet lab validation to identify transcriptional effectors of VSMC-MAPK14, which we previously reported to promote AAA. Compared with wild-type (WT) mice, VSMC-\n                    <jats:italic>Mapk14<\/jats:italic>\n                    knockout (KO) mice displayed reduced VSMC degeneration, as evidenced by decreased expression of markers of endoplasmic reticulum stress, the unfolded protein response, fibrosis, and apoptosis, after 7 days of Ang II infusion. SnRNA-seq revealed increased VSMCs and reduced fibroblast and immune cell populations in KOs. Reclustering VSMCs revealed an increased proportion of contractile cluster and a reduced proportion of fibrotic cluster in KOs. The VSMC differentiation gene program and upstream pathways were upregulated, whereas degeneration pathways, including extracellular matrix remodeling, inflammation, and apoptosis, were downregulated in KO VSMCs. snATAC-seq and validation revealed increased serum response factor (SRF) motif activity and expression but reduced RUNX2 expression in KO VSMCs. Integrative analysis of snATAC-seq, ChIP-seq, and bulk RNA-seq identified the MYOCD\/SRF\/CArG triad as the driver of the contractile gene program following\n                    <jats:italic>Mapk14<\/jats:italic>\n                    loss. We further found that the expression of\n                    <jats:italic>Bcl2<\/jats:italic>\n                    , a novel MYOCD\/SRF\/CArG target, was increased in\n                    <jats:italic>Mapk14<\/jats:italic>\n                    KO VSMCs. Loss of\n                    <jats:italic>Mapk14<\/jats:italic>\n                    attenuated MRTFA protein abundance via increased ubiquitin\u2012proteasome degradation, which was attributed to reduced USP10 protein expression. These findings reveal MAPK14-driven transcriptomic and epigenomic landscapes that promote VSMC degeneration by suppressing SRF\/MYOCD\/CArG while activating RUNX2 and MRTFA. Our study provides mechanistic insight into MAPK14-mediated VSMC degeneration and provides a basis for MAPK14-targeted therapeutic strategies for AAA.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02540-0","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T12:24:23Z","timestamp":1768220663000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["MAPK14 converges on key transcriptional machinery to promote vascular smooth muscle cell degeneration in abdominal aortic aneurysm"],"prefix":"10.1038","volume":"11","author":[{"given":"Xiaoliang","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6379-4109","authenticated-orcid":false,"given":"Nestor","family":"Ishimwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaser","family":"Doja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengshuai","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6056-1537","authenticated-orcid":false,"given":"Yong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micah","family":"Castillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Sotonyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergo","family":"Gyurok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor","family":"Csanyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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