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Over time, senescent cells accumulate and contribute to the progression of multiple age\u2010related degenerative diseases. It is believed that these cells accumulate partly due to their ability to evade programmed cell death through the development and activation of survival and antiapoptotic resistance mechanisms; however, many aspects of how these survival mechanisms develop and activate are still unknown. By analyzing transcriptomic signature profiles generated by the LINCS L1000 project and using network\u2010based methods, we identified various genes that could represent new senescence\u2010related survival mechanisms. Additionally, employing the same methodology, we identified over 600 molecules with potential senolytic activity. Experimental validation of our computational findings confirmed the senolytic activity of Fluorouracil, whose activity would be mediated by a multitarget mechanism, revealing that its targets AURKA, EGFR, IRS1, SMAD4, and KRAS are new senescent cell antiapoptotic pathways (SCAPs). The development of these pathways could depend on the stimulus that induces cellular senescence. The SCAP development and activation mechanisms proposed in this work offer new insights into how senescent cells survive. Identifying new antiapoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively.<\/jats:p>","DOI":"10.1111\/febs.17402","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T23:54:35Z","timestamp":1738022075000},"page":"1950-1971","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Transcriptomic signatures and network\u2010based methods uncover new senescent cell anti\u2010apoptotic pathways and senolytics"],"prefix":"10.1111","volume":"292","author":[{"given":"Samael","family":"Olascoaga","sequence":"first","affiliation":[{"name":"Posgrado en Biolog\u00eda Experimental, DCBS Universidad Aut\u00f3noma Metropolitana Iztapalapa  Mexico City Mexico"},{"name":"Laboratorio de Bioenerg\u00e9tica y Envejecimiento Celular, Departamento de Ciencias de la Salud Universidad 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