Macrocyclic diterpenoids from Stellera chamaejasme roots alleviate imiquimod‐induced psoriasiform inflammation via STAT1/S100A9 signalling pathway

Background and Purpose Psoriasis is a multisystem inflammatory disease with a significant impact on quality of life. Stellera chamaejasme , a medicinal plant used in traditional Chinese medicine, shows promise for the treatment of psoriasis. We identified diterpenoids in S. chamaejasme , including a new compound, stellchamain A (SA, 1 ), with notable antipsoriasis properties. This study explored the effects of SA on psoriasis to determine the mechanisms underlying the therapeutic efficacy of S. chamaejasme . Experimental Approach Compounds isolated by column chromatography were structurally identified using NMR spectroscopy. The effects of SA on IL‐17A‐treated HaCaT cell viability and apoptosis were assessed using CCK‐8 and TUNEL assays. In vivo anti‐psoriasis activity of SA was evaluated in a mouse model of imiquimod (IMQ)‐induced psoriasis. Network pharmacology, surface plasmon resonance (SPR), drug affinity responsive target stability (DARTS), and cellular thermal shift assays (CETSA) were elucidated the interactions between SA and the targets. Key Results SA was isolated from S. chamaejasme along with nine known analogues ( 2 – 10 ). In vivo, SA reduced IMQ‐induced epidermal thickness, hyperkeratosis, and perivascular inflammatory cell infiltration. Network pharmacology indicated that SA may function via the interleukin IL‐17A/STAT1/S100A9 pathway. The results of SPR assays and molecular docking showed that SA binds to STAT1 with a K D value of 9.24 nM. DARTS and CETSA analyses confirmed a direct and relevant interaction between SA and STAT1. Conclusion and Implications SA modulates the immunological microenvironment to treat psoriasis by targeting the IL‐17A/STAT1/S100A9 axis, representing a potential new treatment for psoriasis and other IL‐17A‐mediated skin disorders.