MAGL Inhibition Relieves Psoriasiform Inflammation and Pruritus Via Modulation of ALOX12-12-HETE Axis in Mice.

The endogenous cannabinoid system, comprising endocannabinoids, cannabinoid receptors, and enzymes responsible for synthesis and degradation of endocannabinoids, is integral to the regulation of skin inflammation. However, the precise contributions of cannabinoid-metabolizing enzymes including fatty acid amide hydrolase and monoacylglycerol lipase (MAGL) remain poorly defined in psoriatic pathogenesis. In this study, we demonstrated the significant MAGL upregulation in psoriatic lesions and established that pharmacological inhibition of MAGL markedly reduced psoriasiform inflammation and pruritus in imiquimod-challenged C57BL/6 mice. Mechanically, inhibition of MAGL decreased the expression of 12-lipoxygenase (ALOX12), subsequently reducing the synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE), which is the principal metabolite of ALOX12. Importantly, these effects were reversed by cannabinoid receptor 2 (CB2R) antagonism or knockout, establishing a signaling axis in which MAGL inhibition activates CB2R to suppress ALOX12. Collectively, our findings identified MAGL as a potentially targetable nexus in psoriasiform inflammation and itch. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10753-025-02383-5.