Yifei Wang,1,* Xunhuang Duan,1,* Zhiqi Li,2,* Yuanming Pan,2 Jianhua Deng1 

1Department of Oncology, Jiujiang City Key Laboratory of Cell Therapy, Jiujiang No. 1 People’s Hospital, Jiujiang, Jiangxi, 332001, People’s Republic of China; 2Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jianhua Deng, Department of Oncology, Jiujiang City Key Laboratory of Cell Therapy, Jiujiang No. 1 People’s Hospital, No. 48 Taling South Road, Xunyang District, Jiujiang, Jiangxi, 332001, People’s Republic of China, Tel/Fax +86-792-8171670, Email dengjianhua248@126.com Yuanming Pan, Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 9 Beiguan Street, Yongshun Town, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel/Fax +86-10-89509372, Email peterfpan2020@mail.ccmu.edu.cn

Abstract: Palmitoylethanolamide (PEA) has attracted increasing attention from researchers as an endogenous lipid mediator. It exhibits a unique mechanism of action in alleviating pain, controlling inflammation, and providing neuroprotection. It primarily regulates downstream signaling pathways by activating peroxisome proliferator-activated receptor alpha (PPAR-α) to inhibit the activity of nuclear factor kappa B (NF-κB), thereby reducing the production of pro-inflammatory cytokines. Additionally, PEA interacts synergistically with the endogenous cannabinoid system to modulate neurotransmission by enhancing the function of endogenous cannabinoids. The anti-inflammatory effects of PEA are also reflected in the regulation of glial cells and mast cells, effectively reducing local and central inflammation, thus protecting neuronal cells and promoting their regeneration. Clinical studies have shown that the application of PEA in various types of pain demonstrates good safety and tolerability, particularly suited for use in combination with traditional analgesics to enhance efficacy, reduce dependence, and minimize side effects. Despite existing research proving the effectiveness of PEA, challenges remain in its clinical promotion, including dosage form diversity, overall insufficient evidence, and patient individual differences. Therefore, future efforts should focus on strengthening multi-center large sample randomized controlled trials, coupled with biomarker investigations for personalized treatment research, to facilitate the widespread application of PEA in clinical pain management.

Keywords: palmitoylethanolamide, pain management, inflammation, neuroprotection, clinical applications