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

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.