A Topical Chinese Herbal Alleviates Psoriasis by Regulating Keratinocytes Pyroptosis Through Inhibition of NLRP3 Inflammasome Activation

Purpose: Psoriasis is a chronic inflammatory skin disease involving complex immune dysregulation, where NLRP3 inflammasome-mediated pyroptosis-a pro-inflammatory programmed cell death-has been identified as a key driver of disease pathogenesis. Qingshi anti-itch ointment (QS), a traditional Chinese medicine used for psoriasis, has demonstrated clinical efficacy; however, its specific impact on the NLRP3-pyroptosis pathway remains unclear. This study therefore aims to elucidate the role and underlying mechanisms of QS in regulating NLRP3 inflammasome activation in keratinocytes. Methods: Psoriasis models were established using both in vivo and in vitro approaches: (1) a mouse model induced by topical application of Imiquimod (IMQ) cream, and (2) a cellular model of keratinocyte pyroptosis stimulated with Lipopolysaccharide (LPS) and Adenosine triphosphate (ATP) in vitro. Therapeutic effects were evaluated through Psoriasis area and severity index (PASI) scoring and Hematoxylin-Eosin staining method (HE). NLRP3 inflammasome-mediated pyroptosis was assessed by IHC, RT-qPCR, and Western blot. Levels of IL-18, IL-1β, IL-17, and IL-22 were measured. Transmission electron microscopy was employed to examine NHEK cellular ultrastructure and pyroptotic status. MCC950, a specific NLRP3 inhibitor, was used to determine whether QS modulates keratinocyte pyroptosis through NLRP3 inflammasome regulation. Results: QS effectively ameliorated IMQ-induced psoriasiform lesions by suppressing keratinocyte pyroptosis and maintaining cellular integrity. Both in vivo and in vitro experiments demonstrated QS's ability to inhibit the NLRP3 signaling pathway and selectively regulate key pyroptotic molecules (Caspase-1/GSDMD), thereby reducing proinflammatory cytokine release. Notably, QS combined with MCC950 exhibited significant synergistic effects in suppressing NLRP3 inflammasome activation in both IMQ-induced and LPS/ATP-stimulated models. Conclusion: QS primarily alleviates psoriasis by modulating keratinocyte pyroptosis through mitochondrial protection, inhibition of GSDMD-mediated membrane perforation, and downregulation of Caspase-1 activity, collectively attenuating inflammatory responses. These findings provide novel mechanistic insights into QS's anti-psoriatic effects and may facilitate the development of innovative therapeutic strategies for psoriasis.