Uncovering the bidirectional molecular pathway: How shugan wendan decoction treats concurrent depression and atherosclerosis.

Shugan Wendan Decoction (SGWDD) is a herbal remedy effective against atherosclerosis and depression, yet its mechanism for treating both conditions is not fully understood. This study seeks to confirm the molecular link between depression and atherosclerosis and to explore how SGWDD alleviates this comorbidity. We used a chronic unpredictable mild stress (CUMS) animal model with a high-fat diet (HFD) and a THP-1 foam cell model to investigate the CASP1- and MMP9-mediated "Lipid and Atherosclerosis Pathway" and "Tryptophan Metabolism Pathway" linking depression and atherosclerosis. The therapeutic effects of SGWDD on this comorbidity were evaluated and its impact on the bidirectional mechanisms was identified through intragastric administration and SGWDD-medicated serum. Behavioral tests, LC-MS/MS, serological assays, pathological staining, qPCR, Western blot, immunohistochemical staining, molecular docking, and molecular dynamics simulation were utilized. In vivo, HFD intervention increased serum LDL-C, TC, and arterial NLRP3, CASP1, MMP9, IL-1β, IL-18, and IDO, leading to preatherosclerotic lesions. CUMS intervention impaired behavioral performance, raised serum ACTH and cortisol, and lowered serum 5-HT and hepatic ATF3, LDLR, and CYP7A1. Atherosclerosis and depression may exacerbate each other's pathological progression, with CASP1 and MMP9 serving as key regulatory factors. Dysregulation of CASP1 and MMP9 can affect downstream molecules such as IL-1β and IDO, increasing susceptibility to atherosclerosis and depression. SGWDD can ameliorate both atherosclerosis and depression concurrently. Mechanistically, this herbal compound can inhibit the expression of CASP1 and MMP9, leading to alterations in downstream pathways. Depression may exacerbate the progression of atherosclerosis through the "Lipid and Atherosclerosis Pathway," while atherosclerosis may heighten the susceptibility to depression by perturbing the "Tryptophan Metabolism Pathway." SGWDD exhibits efficacy in managing this comorbidity, partly attributable to its capacity to inhibit CASP1 and MMP9.