ABSTRACT: Clinical studies have demonstrated the anti-psoriatic effect of the LiangXueJieDu (LXJD) herbal formula. However, the systemic mechanism and the targets of the LXJD formula have not yet been elucidated. In the present study, a systems pharmacology approach, metabolomics, and experimental evaluation were employed. First, by systematic absorption-distribution-metabolism-excretion (ADME) analysis, 144 active compounds with satisfactory pharmacokinetic properties were identified from 12 herbs of LXJD formula using the TCMSP database. These active compounds could be linked to 125 target proteins involved in the pathological processes underlying psoriasis. Then, the networks constituting the active compounds, targets, and diseases were constructed to decipher the pharmacological actions of this formula, indicating its curative effects in psoriasis treatment and related complications. The psoriasis-related pathway comprising several regulatory modules demonstrated the synergistic mechanisms of LXJD formula. Furthermore, the therapeutic effect of LXJD formula was validated in a psoriasis-like mouse model. Consistent with the systems pharmacology analysis, LXJD formula ameliorated IMQ-induced psoriasis-like lesions in mice, inhibited keratinocyte proliferation, improved keratinocyte differentiation, and suppressed the infiltration of CD3+ T cells. Compared to the model group, LXJD formula treatment remarkably reduced the expression of inflammatory cytokines and factors, such as IL-1β, IL-6, TNF-α, Cox2, and inhibited the phosphorylation of p-P65, p-IқB, p-ERK, p-P38, p-PI3K, p-AKT, indicating that LXJD formula exerts its therapeutic effect by inhibiting the MAPK, PI3K/AKT, and NF-қB signaling pathways. The metabolic changes in the serum of psoriasis patients were evaluated by liquid chromatography coupled with orbitrap mass spectrometry (LC-MS). The LXJD formula improved two perturbed metabolic pathways of glycerophospholipid metabolism and steroid hormone biosynthesis. Overall, this study revealed the complicated anti-psoriatic mechanism of LXJD formula and also offered a reliable strategy to elucidate the complex therapeutic mechanism of this Chinese herbal formula in psoriasis from a holistic perspective.
