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It is well known that the activation of p38 mitogen-activated protein kinase (p38 MAPK) orchestrates senescence in CD8<jats:sup>+<\/jats:sup> T lymphocytes. However, p38 MAPK contribution to CD4<jats:sup>+<\/jats:sup> T lymphocyte senescence remains less comprehensively characterized and warrants further investigation. This study investigates the contribution of p38 MAPK to senescence in CD4<jats:sup>+<\/jats:sup> T lymphocytes, focusing on mitochondrial dysfunction and SASP production to elucidate their pathological potential.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Splenic CD4<jats:sup>+<\/jats:sup> T lymphocytes isolated from wild-type C57BL\/6 mice were subjected to subcytotoxic oxidative stress by H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> exposure to generate stress-induced premature senescence. H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-exposed CD4<jats:sup>+<\/jats:sup> T lymphocytes exhibited hallmark features of senescence, including increased cell size, reduced cell proliferation, and upregulation of the cell cycle regulators p16<jats:sup>Ink4a<\/jats:sup> and p21<jats:sup>Cip1<\/jats:sup>. Additionally, these cells displayed defective mitophagy, accumulation of dysfunctional mitochondria, and a SASP enriched in Th17-associated cytokines. In senescence-induced CD4<jats:sup>+<\/jats:sup> T lymphocytes, an increase in the expression of phospho-p38 MAPK was also detected. The senescence changes were reversed when p38 MAPK was blocked using the specific inhibitor BIRB-796. In particular, neutralizing p38 MAPK reduced mitochondrial dysfunction and Th17-type SASP production, demonstrating its critical role in driving these senescent traits in CD4<jats:sup>+<\/jats:sup> T lymphocytes. These findings ratify the involvement of p38 MAPK as a central regulator of CD4<jats:sup>+<\/jats:sup> T lymphocyte senescence, particularly concerning the accumulation of dysfunctional mitochondria and pro-inflammatory SASP production.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study provides critical insights into immune aging mechanisms in CD4<jats:sup>+<\/jats:sup> T lymphocytes and underscores the therapeutic potential of targeting p38 MAPK to mitigate senescence-driven inflammatory diseases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12979-025-00526-8","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T07:04:05Z","timestamp":1752563045000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["p38 mitogen-activated protein kinase drives senescence in CD4+ T lymphocytes and increases their pathological potential"],"prefix":"10.1186","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8456-6372","authenticated-orcid":false,"given":"Luis","family":"Gonz\u00e1lez-Osuna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6589-4784","authenticated-orcid":false,"given":"Sandra Yasuyo","family":"Fukada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2365-9652","authenticated-orcid":false,"given":"Mar\u00eda Paz","family":"Hern\u00e1ndez-C\u00e1ceres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0067-7743","authenticated-orcid":false,"given":"Patricia","family":"Luz-Crawford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1887-0808","authenticated-orcid":false,"given":"Cristian","family":"Cortez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4004-3999","authenticated-orcid":false,"given":"Carolina","family":"Rojas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5045-4412","authenticated-orcid":false,"given":"Paola","family":"Carvajal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0952-9835","authenticated-orcid":false,"given":"Alfredo","family":"Sierra-Cristancho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1391-320X","authenticated-orcid":false,"given":"Rolando","family":"Vernal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"issue":"6","key":"526_CR1","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.tcb.2018.02.001","volume":"28","author":"A Hernandez-Segura","year":"2018","unstructured":"Hernandez-Segura A, Nehme J, Demaria M. 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