Naaa, also known as N-Acylethanolamine acid amidase, is an N-terminal cysteine hydrolase. It is mainly located in the endosomal-lysosomal compartment of immune cells. Naaa catalyzes the hydrolytic deactivation of palmitoylethanolamide (PEA), a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist with anti-inflammatory effects. Naaa-regulated PEA signaling at PPAR-α is a crucial control point for inflammation induction and resolution, making Naaa a potential target for anti-inflammatory drugs [1].

In mouse models, several key findings have emerged. Deletion of the Naaa gene or pharmacological inhibition of NAAA activity significantly attenuated dopamine neuron death and parkinsonian symptoms in mice treated with mitochondrial neurotoxins [3]. Mice lacking Naaa in CD11b+ cells (monocytes, macrophages, and neutrophils) were resistant to the induction of hyperalgesic priming, indicating that Naaa-regulated signaling in monocytes is a control node in the transition to chronic pain [2]. In a traumatic brain injury (TBI) model, inactivation of Naaa increased PEA levels, prevented early blood-brain-barrier (BBB) damage, and improved secondary injury [4]. In a psoriasis model, genetic ablation of Naaa or local administration of its inhibitor ameliorated psoriasis by reducing dendritic cell maturation [5].

In conclusion, Naaa plays a significant role in multiple biological processes and disease conditions. Studies using gene knockout or pharmacological inhibition of Naaa in mouse models have revealed its importance in inflammation, pain, Parkinson's disease, TBI, and psoriasis. These findings suggest that targeting Naaa could be a promising strategy for treating these diseases.