Curcumin alleviates depression-aggravated psoriasis by targeting MMP9-regulated apoptotic pathways

<h2>Summary</h2> Depression and psoriasis are highly comorbid, yet their shared molecular mechanisms remain poorly understood. Utilizing cross-sectional data from NHANES and Mendelian randomization (MR), a significant association and causal link between depression and psoriasis were established. A combined mouse model of chronic unpredictable mild stress (CUMS) and imiquimod-induced psoriasis confirmed that depressive state exacerbates psoriasis-like skin lesions. Integrated multi-omics analyses (including bulk and single-cell RNA sequencing, machine learning, and eQTL/pQTL-MR) identified apoptosis as a key shared pathway, with matrix metallopeptidase 9 (MMP9) as a central causal gene. Animal experiments confirmed MMP9 upregulation in both skin and brain tissues. Molecular docking predicted strong binding of curcumin to MMP9, and subsequent <i>in vivo</i> intervention demonstrated that curcumin downregulated MMP9 expression and alleviated both pathological conditions. These findings reveal MMP9-mediated apoptosis as a central pathological link in the comorbidity of depression and psoriasis and suggest a dual-treatment strategy for this comorbidity.