Sihe Tufuling formula alleviates imiquimod-induced psoriasis-like skin lesions in mice by modulating the HIF-1 signaling pathway.

Abstract

OBJECTIVE: Psoriasis is a chronic, immune-mediated dermatological disorder characterized by pathological epidermal hyperplasia, aberrant keratinocyte differentiation, and dermal infiltration of inflammatory cells. Sihe Tufuling (SHTFL), a clinically established traditional Chinese medicine formula, has demonstrated therapeutic efficacy in psoriasis management. This study aimed to investigate the anti-psoriatic activity of SHTFL and its principal herb, Smilax glabra Roxb. (SGR), and to elucidate their underlying mechanisms of action. METHODS: Ultra-performance liquid chromatography-mass spectrometry was used to identify the major chemical constituents of SHTFL and SGR. An imiquimod (IMQ)-induced psoriasis-like mouse model was employed to assess therapeutic efficacy using the psoriasis area and severity index, spleen index, hematoxylin and eosin staining, immunohistochemistry, immunofluorescence. Transcriptomic sequencing, single-cell RNA sequencing, gene knockdown, immunofluorescence, and quantitative reverse-transcription PCR analyses were performed to investigate the molecular mechanisms involved. RESULTS: The results of the chemical component identification indicated that flavonoids constitute essential components in both the SHTFL formula and SGR. Treatment with SHTFL and SGR resulted in a significant reduction of the PASI score, skin thickness, splenic index and serum levels of inflammatory cytokines in IMQ-induced mice psoriasis mice. Moreover, both SHTFL and SGR alleviated psoriasis by inhibiting keratinocyte hyperproliferation and the inflammatory response in IMQ-induced mice. Transcriptomic analysis revealed that SHTFL and SGR mitigates keratinocyte hyperproliferation and the inflammatory response by modulating the HIF-1 signaling pathway. Furthermore, HIF-1α knockdown abolished the protective effects of SHTFL in these models. CONCLUSION: Our results indicate that both SHTFL and SGR hinder the excessive growth of keratinocytes and reduce inflammation in psoriasis by inhibiting the HIF-1 signaling pathway. This evidence backs SHTFL as a promising therapeutic approach for psoriasis.