{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:09:24Z","timestamp":1785427764875,"version":"3.56.0"},"posted":{"date-parts":[[2025,7,31]]},"group-title":"Cell Biology","reference-count":37,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["ZIA BC 011496"],"award-info":[{"award-number":["ZIA BC 011496"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["ZIA TR 000052"],"award-info":[{"award-number":["ZIA TR 000052"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Patients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, have been developed, further efforts to explore mechanistically distinct and complementary strategies are still critical to better treatment regimens. We previously showed that lentiviral vector-driven expression of \u0394133p53\u03b1, a natural inhibitory isoform of p53, rescued HGPS patients-derived fibroblasts from early entry into cellular senescence, which is a downstream event of progerin-induced DNA damage. We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate \u0394133p53\u03b1 protein levels.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    To investigate whether celastrol and ADZ1981 upregulate endogenous \u0394133p53\u03b1 in HGPS-derived fibroblasts and reduce their senescence-associated phenotypes, we performed western blot assays (\u0394133p53\u03b1, progerin, and p21\n                    <jats:sup>WAF1<\/jats:sup>\n                    , which mediates p53-induced senescence and is inhibited by \u0394133p53\u03b1), senescence-associated \u03b2-galactosidase (SA-\u03b2-gal) staining, enzyme-linked immunosorbent assay (IL-6, which is a proinflammatory cytokine secreted from senescent cells), and qRT-PCR assays (p21\n                    <jats:sup>WAF1<\/jats:sup>\n                    and IL-6).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Treatment with celastrol (0.1 \u00b5M for 24 h) or AZD1981 (10 \u00b5M for 24 h) reproducibly increased \u0394133p53\u03b1 expression and decreased p21\n                    <jats:sup>WAF1<\/jats:sup>\n                    expression in two strains of fibroblasts derived from HGPS patients. These compounds reduced the percentage of SA-\u03b2-gal-positive senescent cells and the secretion of IL-6 into culture medium in both of these fibroblast strains, irrespective of their different basal levels of senescence and IL-6 secretion. These compounds had no effect on the level of progerin.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Celastrol and ADZ1981 upregulate endogenous \u0394133p53\u03b1 and, reproducing the effects of its vector-driven expression, inhibit cellular senescence and IL-6 secretion in HGPS-derived fibroblasts. Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which \u0394133p53\u03b1-regulated senescence plays a role.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.28.667224","type":"posted-content","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T02:35:25Z","timestamp":1754015725000},"source":"Crossref","is-referenced-by-count":0,"title":["Pharmacologic activation of \u0394133p53\u03b1 reduces cellular senescence in progeria patients-derived cells"],"prefix":"10.64898","author":[{"given":"Sebastien M.","family":"Joruiz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Lissa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Von 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