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Current therapies lack prophylactic effectiveness and often fail to achieve an optimal immunological balance between inflammation and immunosuppression. In this study, we investigated the effects of palmitoylethanolamide (PEA), an endocannabinoid\u2010like lipid mediator with extensively documented anti\u2010inflammatory, analgesic, antimicrobial, immunomodulatory, and neuroprotective effects, on the complex pathology of GVHD. Treatment with PEA reduced clinical disease severity in GVHD mice, leading to an 80% increase in survival rates. Additionally, PEA created an immunoregulatory environment in the spleen by reducing the activation of CD3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> cells. In the intestine, PEA protected against damage, reduced the number of CD3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> and CD3<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> cells, and suppressed the activation of CD3<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> cells. PEA also decreased the levels of TNF\u2010\u03b1 in the intestine and increased IL\u201010 production. Furthermore, in the liver, PEA treatment reduced the number of CD8<jats:sup>+<\/jats:sup> cells, the activation of CD3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> and CD3<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> cells, and TNF\u2010\u03b1 levels. The effect of PEA on survival was dependent on Peroxisome Proliferator\u2010activated receptor gamma (PPAR\u2010\u03b3) activation but did not rely on cannabinoid (CB) receptors activation. In addition to GVHD protection, PEA treatment did not interfere in the graft\u2010versus\u2010tumour response. These results demonstrate the therapeutic potential of PEA as a promising option for the treatment of GVHD, balancing inflammation and immunosuppression, and improving both survival and clinical outcomes.<\/jats:p>","DOI":"10.1111\/imm.70010","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:35:47Z","timestamp":1750898147000},"page":"385-402","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Palmitoylethanolamide (<scp>PEA<\/scp>) Induces an Increase in Spleen Regulatory T Cells, Reduces <scp>CD8<\/scp><sup>+<\/sup> Cells and <scp>TNF<\/scp>\u2010\u03b1 Levels in Target Organs, and Protects Mice From Graft\u2010Versus\u2010Host Disease\u2010Related Mortality Through <scp>PPAR<\/scp> Activation Without Compromising the Graft\u2010Versus\u2010Tumour Response"],"prefix":"10.1111","volume":"176","author":[{"given":"B\u00e1rbara 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