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Progerin anchors aberrantly to the nuclear envelope disrupting a plethora of cellular processes, which in turn elicits senescence. We previously showed that the chromosomal region maintenance 1 (CRM1)\u2010driven nuclear export pathway is abnormally enhanced in patient\u2010derived fibroblasts, due to overexpression of CRM1. Interestingly, pharmacological inhibition of CRM1 using leptomycin B rescues the senescent phenotype of HGPS fibroblasts, delineating CRM1 as a potential therapeutic target against HGPS. As a proof of concept, we analyzed the beneficial effects of pharmacologically modulating CRM1 in dermal fibroblasts from HGPS patients and the <jats:italic>LMNA<jats:sup>G609G\/G609G<\/jats:sup><\/jats:italic> mouse, using the first\u2010in\u2010class selective inhibitor of CRM1 termed selinexor. Remarkably, treatment of HGPS fibroblasts with selinexor mitigated senescence and promoted progerin clearance via autophagy, while at the transcriptional level restored the expression of numerous differentially\u2010expressed genes and rescued cellular processes linked to aging. In\u00a0vivo, oral administration of selinexor to the progeric mouse resulted in decreased progerin immunostaining in the liver and aorta, decreased progerin levels in most liver, lung and kidney samples analyzed by immunoblotting, and improved aortic histopathology. Collectively our data indicate that selinexor exerts its geroprotective action by at least two mechanisms: normalizing the nucleocytoplasmic partition of proteins with a downstream effect on the aging\u2010associated transcriptome and decreasing progerin levels. Further investigation of the overall effect of selinexor on <jats:italic>Lmna<jats:sup>G609G\/G609G<\/jats:sup><\/jats:italic> mouse physiology, with emphasis in cardiovascular function is warranted, to determine its therapeutic utility for HGPS and aging\u2010associated disorders characterized by CRM1 overactivity.<\/jats:p>","DOI":"10.1111\/acel.14495","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T01:49:26Z","timestamp":1738028966000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Targeting <scp>CRM1<\/scp> for Progeria Syndrome Therapy"],"prefix":"10.1111","volume":"24","author":[{"given":"Adriana","family":"Soto\u2010Ponce","sequence":"first","affiliation":[{"name":"Departamento de Gen\u00e9tica y Biolog\u00eda Molecular Centro de Investigaci\u00f3n y de Estudios Avanzados  Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlon","family":"De Ita","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica y Biolog\u00eda Molecular Centro de Investigaci\u00f3n y de Estudios Avanzados  Ciudad de M\u00e9xico Mexico"},{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Gen\u00e9tica Humana, Hospital de Pediatr\u00eda, Centro M\u00e9dico Nacional Siglo XXI, IMSSS  Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0549-5690","authenticated-orcid":false,"given":"Susana","family":"Castro\u2010Obreg\u00f3n","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Celular, UNAM, Ciudad Universitaria  Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Cortez","sequence":"additional","affiliation":[{"name":"Centro de Ciencias Gen\u00f3micas, UNAM  Cuernavaca Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosef","family":"Landesman","sequence":"additional","affiliation":[{"name":"Karyopharm Therapeutics  Newton Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan J.","family":"Maga\u00f1a","sequence":"additional","affiliation":[{"name":"Laboratorio de Medicina Gen\u00f3mica, Departamento de Gen\u00e9tica (CENIAQ) Instituto Nacional de Rehabilitaci\u00f3n\u2010Luis Guillermo Ibarra (INR\u2010LGII)  Ciudad de M\u00e9xico Mexico"},{"name":"Departamento de Bioingenier\u00eda Escuela de Ingenier\u00eda y Ciencias, Tecnologico de Monterrey  Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9631-1206","authenticated-orcid":false,"given":"Susana","family":"Gonzalo","sequence":"additional","affiliation":[{"name":"Edward A. 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