Abstract: OBJECTIVE To study the effect of endogenous pro-inflammatory lipid palmitoylethanolamide on sleep deprivation-induced dry eye in mice. METHODS Sleep deprivation-induced mouse model was established by "stick over water" and last for 20 h every day. PPAR-α gene and protein expression were detected in lacrimal gland tissues of 5, 10 d model group and normal group. The expression of palmitoylethanolamide and the related synthetic enzyme NAPEPLD and metabolizing enzyme NAAA were also detected; cetylethanolamine and its solvent were administered respectively, the lacrimal gland, tear secretion, corneal injury and expression of conjunctival goblet cells were detected, histopathological changes of lacrimal gland were evaluated. RESULTS Compared with the normal group, the expression of cetylethanolamine and its receptor PPAR-α in the lacrimal gland tissue of the mice in the model group was significantly decreased, the expression of the synthase NAPEPLD was decreased, and the gene expression of the degrading enzyme NAAA was increased. Compared with the blank solvent treatment group, cetylethanolamine could increase the secretion of tears in sleep-deprived mice, reduce corneal damage, and significantly increase the number of conjunctival goblet cells, improve the lipid deposition and pathological changes in the lacrimal gland tissue of model mice, and maintain the basic skeleton of the lacrimal gland.CONCLUSION Palmitoylethanolamide can improve sleep deprivation induced dry eye in mice.