Unveiling the Novel Multitarget Antidepressant Mechanisms of Ligustilide in Postpartum Depression: An Integrative Network Pharmacology and Molecular Simulation Study

ABSTRACT Ligustilide (LIG) has a promising potential for the treatment of postpartum depression (PPD) as preclinical evidence supports its antidepressant effects; however, its precise mechanism in PPD remains unclear. This study is the first PPD‐focused computational work to provide a system‐level analysis of LIG using an integrative network pharmacology, ADMET, molecular docking, and dynamics simulations framework. Common targets between LIG and PPD were screened by VENNY 2.1 web tool and further analyzed via PPI networks, followed by GO/KEGG enrichment. A total of 170 common targets were identified between LIG and PPD. in silico predicted ADMET profiling indicated that LIG possesses favorable CNS permeability and low predicted acute toxicity but may have limited oral bioavailability. GO and KEGG analysis indicate significant enrichment in the CLR, endocrine resistance, FOXO, HIF‐1, IL‐17, PI3K‐Akt, and TNF signaling pathways. Molecular docking studies revealed LIG moderate binding affinities with PPARG (−7.323 kcal/mol), ESR1 (−7.054 kcal/mol), PTGS2 (−7.024 kcal/mol), and TNF (−6.959 kcal/mol). MD simulations of 100 ns confirmed the specificity of these interactions through post‐MD simulation interaction diagram, supporting a multi‐node modulatory role across neuroendocrine and neuroimmune axes. These results provide a mechanistic foundation for future in vitro and in vivo experimental validation.