Xiegan Liangxue Jiedu Decoction ameliorates psychiatric comorbidities in psoriasis via regulation of sphingolipid metabolism.

Xiegan-Liangxue-Jiedu decoction (XLJD) is an ethnopharmacological empirical prescription inherited from Gu's Surgery, a national intangible cultural heritage of Chinese ethnomedicine. Developed based on the classic TCM theory of Liver governing emotion, XLJD has been clinically used for centuries to treat psoriasis (PsO) via the principle of the TCM principle of "treating PsO from the Liver perspective", and has shown favorable efficacy in alleviating psychiatric comorbidities in psoriasis (PCP) by soothing the Liver and relieving emotional discomfort. To determine the therapeutic efficacy of XLJD and its potential mechanisms of action in PCP mice, and to reveal the modern pharmacological mechanism of the TCM theory of Liver governing emotion in the treatment of PCP. Mass spectrometry were used to elucidate XLJD's phytochemical profile and blood-absorbed components. The murine PCP model was established by exposure to CUMS and imiquimod. The efficacy of treating PsO was evaluated using PASI, HE staining, lymphocyte proliferation levels, cytokine levels, etc. Mental disorders were evaluated using the open field, elevated plus maze, and tail suspension tests. RNA-seq was performed to detect transcriptional changes in skin tissues, while lipidomics was applied to analyze serum lipids. Key genes and protein were validated using qPCR and Western-blotting, respectively. Acid sphingomyelinase (ASM) and M1/M2 microglia in the hippocampus were determined via immunofluorescence staining. Among the 142 compounds identified in XLJD, 21 were detected in the blood. XLJD significantly alleviated the severity of PsO-related indicators in PCP mice while ameliorating behavioral abnormalities and mitigating HPA axis hyperactivity. XLJD downregulated the transcription of genes involved in lipid metabolism and ameliorated abnormal sphingolipid (SP) metabolism. It inhibited lesions mediated by sphingosine-1-phosphate signaling in lesioned skin. In the hippocampus, XLJD reduced the proportion of M1 microglia and exerted potential neuroprotective effects by inhibiting ASM expression and activity. Based on the TCM theory of Liver governing emotion, XLJD alleviated PsO severity and improved associated mental dysfunctions concomitantly in PCP mice by regulating SP metabolism. This study verifies the scientific connotation of the ethnopharmacological principle of treating PsO from the Liver perspective and provides a new ethnopharmacological strategy for the clinical management of PCP.