Jinkui Shenqi decoction targets PAD4 to restrain NETosis and ameliorates psoriasis progression

• Jinkui Shenqi decoction (JKSQD) reversed the progression of psoriasis and restored skin homeostasis in mice. • Proteomics revealed that peptidylarginine deiminase 4 (PAD4) involved in neutrophil extracellular traps (NETs) was significantly downregulated in psoriasis-like mice following treatment of JKSQD. • In vitro/vivo experiments confirmed that JKSQD targets PAD4 to inhibit NETosis. • Metabolomics demonstrated JKSQD influenced D-Arginine and D-ornithine metabolism compared with psoriasis-like and normal mice skin. The underlying pathogenesis of psoriasis was attributed to insufficient kidney qi and blood stasis arising from impeded blood circulation. Jinkui Shenqi decoction (JKSQD), was renowned for its capacity to warm and tonify kidney yang, as well as to invigorate blood circulation. However, there remains a dearth of studies on its specific therapeutic effects and underlying mechanisms of psoriasis. Aiming to investigate the effectiveness and mechanism of JKSQD in the treatment of psoriasis. Initially, we identified the compounds of JKSQD by UPLC-Q-TOF-MS/MS and constructed psoriasis-like mice to explore the effect of JKSQD on psoriasis. Subsequently, proteomic sequencing was conducted to identify key proteins and pathways involved in the therapeutic effect of JKSQD. Neutrophil extracellular traps (NETs) and peptidylarginine deiminase 4 (PAD4)-related indicators were detected to validate JKSQD mechanisms. At last, we analyzed metabolomic data to elucidate what metabolic pathway or metabolites worked during this procedure. We found that JKSQD effectively reversed the progression of psoriasis and associated inflammation in mice. Proteomic analysis further illuminated that PAD4 involved in NETosis was notably downregulated in psoriasis-like mice after JKSQD treatment. And a series of experiments further revealed that JKSQD inhibited NETs formation and PAD4 expression. Moreover, metabolomics demonstrated JKSQD influenced D-Arginine and D-ornithine metabolism, offering deeper insights into the mechanisms of JKSQD on psoriasis. This study unveiled that JKSQD could improve psoriasis progression by targeting PAD4 to inhibit NETs formation.