# Investigating Properties of Palmitoylethanolamide in Physiology and Disease: Far Beyond an Anti-Inflammatory Shield **Authors:** Chiara Veredice, Ida Turrini, Helena Pelanda, Ilaria Contaldo, Donato Rigante PMC · DOI: 10.3390/diseases14020052 · Diseases · 2026-01-31 ## TL;DR This paper explores how palmitoylethanolamide (PEA) helps reduce inflammation and supports cellular health beyond its anti-inflammatory effects. ## Contribution The paper highlights PEA's role in regulating microglia and mast cells, suggesting new therapeutic opportunities for neuroimmune-related diseases. ## Key findings - PEA preserves cellular homeostasis by regulating microglia and inhibiting mast cell activation in the central nervous system. - Ultramicronized PEA formulations improve bioavailability and efficacy for various clinical applications. - PEA shows potential as a broad-spectrum protective agent across multiple tissues. ## Abstract Palmitoylethanolamide (PEA) among N-acylethanolamides displays a noteworthy impact on different inflammatory conditions and promises to become a valuable anti-inflammatory tool that does not interfere with the cyclooxygenase pathway. Mounting evidence confirms the multi-dimensional PEA-mediated crosstalk between microglia and mast cells, which would open new therapeutic opportunities targeting a neuroimmune axis and influencing both health and disease. In particular, PEA acts as a preserver of cellular homeostasis by regulating microglia cell activity and inhibiting mast cell activation in the central nervous system. The improved bioavailability and efficacy of ultramicronized formulations of PEA reflect its ultimate usefulness for different clinical applications, including significantly relieving inflammation but also reducing the pro-inflammatory burden of complex patients with either neuropathies or non-neurologic afflictions. This review aims to comprehensively delineate the therapeutic potential of PEA beyond its mere indication for acute inflammation and to highlight PEA activity as a broad-spectrum pan-tissue protective agent through the results of different preclinical and also some clinical studies. Much more remains to be learned about further PEA mechanisms of action that regulate neuroinflammation, and additional studies will have to investigate the exact role of microglia and mast cells in inflammatory diseases. ## Linked entities - **Chemicals:** Palmitoylethanolamide (PubChem CID 4671) ## Full-text entities - **Genes:** INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, SELP (selectin P) [NCBI Gene 6403] {aka CD62, CD62P, GMP140, GRMP, LECAM3, PADGEM}, STAT6 (signal transducer and activator of transcription 6) [NCBI Gene 6778] {aka D12S1644, HIES6, IL-4-STAT, STAT6B, STAT6C}, CCL22 (C-C motif chemokine ligand 22) [NCBI Gene 6367] {aka A-152E5.1, ABCD-1, DC/B-CK, MDC, SCYA22, STCP-1}, NGF (nerve growth factor) [NCBI Gene 4803] {aka Beta-NGF, HSAN5, NGFB}, NCF1 (neutrophil cytosolic factor 1) [NCBI Gene 653361] {aka CGD1, NCF-1, NCF-47K, NCF1A, NOXO2, SH3PXD1A}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, Mapk14 (mitogen-activated protein kinase 14) [NCBI Gene 26416] {aka CSBP2, Crk1, Csbp1, Mxi2, PRKM14, PRKM15}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, PPARA (peroxisome proliferator activated receptor alpha) [NCBI Gene 5465] {aka NR1C1, PPAR, PPAR-alpha, PPARalpha, hPPAR}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, Nfkbia (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha) [NCBI Gene 18035] {aka Nfkbi}, Jak2 (Janus kinase 2) [NCBI Gene 16452] {aka Fd17}, TNFRSF1A (TNF receptor superfamily member 1A) [NCBI Gene 7132] {aka CD120a, FPF, TBP1, TNF-R, TNF-R-I, TNF-R55}, NFKBIA (NFKB inhibitor alpha) [NCBI Gene 4792] {aka EDAID2, IKBA, MAD-3, NFKBI}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, Il18 (interleukin 18) [NCBI Gene 16173] {aka Igif, Il-18}, HTT (huntingtin) [NCBI Gene 3064] {aka HD, IT15, LOMARS}, SLC2A2 (solute carrier family 2 member 2) [NCBI Gene 6514] {aka GLUT2}, mucin [NCBI Gene 100508689], Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 19013] {aka 4933429D07Rik, Nr1c1, PPAR-alpha, PPARalpha, Ppar}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, IL13 (interleukin 13) [NCBI Gene 3596] {aka IL-13, P600}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, IL12B (interleukin 12B) [NCBI Gene 3593] {aka CLMF, CLMF2, IL-12B, IMD28, IMD29, NKSF}, NCF2 (neutrophil cytosolic factor 2) [NCBI Gene 4688] {aka NCF-2, NOXA2, P67-PHOX, P67PHOX}, TARDBP (TAR DNA binding protein) [NCBI Gene 23435] {aka ALS10, TDP-43}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58} - **Diseases:** Alzheimer's (MESH:D000544), gynecological pain (MESH:D005833), Tourette syndrome (MESH:D005879), brain inflammation (MESH:D004660), diabetic neuropathy (MESH:D003929), vasculopathy (MESH:D000090122), infections (MESH:D007239), fibromyalgia (MESH:D005356), cardiovascular complications (MESH:D002318), neurotoxic (MESH:D020258), retinal gliosis (MESH:D012173), coronavirus disease 2019 (MESH:D000086382), lung damage (MESH:D008171), myocardial ischemia (MESH:D017202), Huntington's disease (MESH:D006816), colitis (MESH:D003092), neoplastic (MESH:D009369), Ischemic stroke (MESH:D002544), post-surgical pain (MESH:D010149), traumatic brain injuries (MESH:D000070642), vascular injury (MESH:D057772), knee osteoarthritis (MESH:D020370), ALI (MESH:D055371), liver fibrosis (MESH:D008103), joint swelling (MESH:D007592), toxicity (MESH:D064420), rheumatological (MESH:D012216), edema (MESH:D004487), Neuroinflammation (MESH:D000090862), neuronal atrophy (MESH:D001284), anxiety (MESH:D001007), injury to (MESH:D014947), neurodegenerative diseases (MESH:D019636), mastocytosis (MESH:D008415), headache (MESH:D006261), Inflammatory (MESH:D007249), epilepsy (MESH:D004827), amyotrophic lateral sclerosis (MESH:D000690), metabolic syndrome (MESH:D024821), ASD (MESH:D000067877), pain (MESH:D010146), demyelinating diseases (MESH:D003711), mast cell deficiency (MESH:D007946), eczema (MESH:D004485), neutrophil (MESH:C564275), Parkinson's disease (MESH:D010300), menstrual pain (MESH:D004412), endometriosis (MESH:D004715), middle cerebral artery occlusion (MESH:D020244), preterm labor (MESH:D007752), ischemia (MESH:D007511), autoinflammatory disorders (MESH:D056660), -neurologic afflictions (MESH:D009461), osteoarthritis (MESH:D010003), autosomal dominantly-inherited disease (MESH:D030342), multiple sclerosis (MESH:D009103), functional dyspepsia (MESH:D004415), frontotemporal dementia (MESH:D057180), episodic migraine (MESH:D008881), allodynia (MESH:D006930) - **Chemicals:** nitroglycerin (MESH:D005996), adelmidrol (MESH:C552602), omega-3 fatty acids (MESH:D015525), prostaglandin (MESH:D011453), isoflavones (MESH:D007529), duloxetine (MESH:D000068736), carbon tetrachloride (MESH:D002251), rutin (MESH:D012431), fatty acid (MESH:D005227), N-acylethanolamides (-), eicosanoids (MESH:D015777), pregabalin (MESH:D000069583), levodopa (MESH:D007980), PEA (MESH:C005958), leukotriene B4 (MESH:D007975), N-acylethanolamine (MESH:C022203), oxygen (MESH:D010100), carrageenan (MESH:D002351), OEA (MESH:C488250), resveratrol (MESH:D000077185), luteolin (MESH:D047311), bleomycin (MESH:D001761), gabapentin (MESH:D000077206), anandamide (MESH:C078814), glucose (MESH:D005947), reactive oxygen species (MESH:D017382), nitrotyrosine (MESH:C002744), lipopolysaccharide (MESH:D008070), lipid (MESH:D008055), endocannabinoid (MESH:D063388), prostaglandin E2 (MESH:D015232) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Malus domestica (apple, species) [taxon 3750], gut metagenome (species) [taxon 749906], Ruminococcus (genus) [taxon 1263], Solanum tuberosum (potatoes, species) [taxon 4113] ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12939291/full.md ## Figures 1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC12939291/full.md ## References 74 references — full list in the complete paper: https://tomesphere.com/paper/PMC12939291/full.md --- Source: https://tomesphere.com/paper/PMC12939291