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Initially considered minor or alternative isoforms, accumulating evidence has revealed distinct and overlapping functions for p38\u03b3 and p38\u03b4 in innate immunity, tissue homeostasis, inflammatory disease, and cancer. These kinases regulate immune responses through diverse mechanisms controlling cytokine production, gene expression, immune-cell activation, and migration. In addition, recent studies suggest that some functions of p38\u03b3 and p38\u03b4 may occur independently of their catalytic activity, highlighting the complexity of their biological roles. The present review summarizes current knowledge of the molecular features, substrates, immune cell functions, and disease associations of p38\u03b3 and p38\u03b4 and discusses their potential as therapeutic targets while addressing the challenges associated with their pharmacological modulation.<\/jats:p>","DOI":"10.1042\/bst20250382","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:52:01Z","timestamp":1791273121000},"page":"1451-1461","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["p38\u03b3 and p38\u03b4 MAP kinases in inflammation"],"prefix":"10.1042","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4233-0943","authenticated-orcid":false,"given":"Ester","family":"D\u00edaz-Mora","sequence":"first","affiliation":[{"name":"Department of Immunology and Oncology, Centro Nacional de Biotecnolog\u00eda (CNB)\/CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6955-2386","authenticated-orcid":false,"given":"Ana","family":"Risco","sequence":"additional","affiliation":[{"name":"Department of Immunology and Oncology, Centro Nacional de Biotecnolog\u00eda (CNB)\/CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9013-5077","authenticated-orcid":false,"given":"Ana","family":"Cuenda","sequence":"additional","affiliation":[{"name":"Department of Immunology and Oncology, Centro Nacional de Biotecnolog\u00eda (CNB)\/CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"2026100603515862600_B1","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1016\/j.bbamcr.2007.03.010","article-title":"p38 MAP-kinases pathway regulation, function and role in human diseases","volume":"1773","author":"Cuenda","year":"2007","journal-title":"Biochim. 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