Major Depressive Disorder (MDD) stands as a prevalent mental health condition encountered in clinical settings, marked by profound and sustained depressive moods and anhedonia. The World Health Organization (WHO) highlighted in 2020 that depression was responsible for 4.3% of the global disease burden (Arias-de la Torre et al., 2021), with projections indicating its ascension to the foremost position in global disease burden by 2030 (Mathers and Loncar, 2006). Research published in Lancet Psychiatry in 2021 revealed a lifetime prevalence of 6.8% for depression among Chinese adults (Lu et al., 2021). Current pharmacological interventions, predominantly Selective Serotonin Reuptake Inhibitors (SSRIs), are hindered by limitations such as low response rates, significant side effects, and pronounced variability in individual outcomes (Rush et al., 2006). In light of these challenges, domestic scholars have increasingly explored Traditional Chinese Medicine (TCM), which boasts extensive historical application and clinical insight into MDD management. TCM is particularly noted for its capacity to address related gastrointestinal, sleep, and sexual dysfunctions with minimal adverse reactions. The inherent complexity and synergistic potential of TCM formulations lend them multi-target, multi-pathway, and multi-systemic therapeutic advantages (Feng et al., 2022).

Kaiyu Zhishen Decoction (KZD), documented by Qing Dynasty physician Chen Shiduo in “Syndrome Differentiation Volume 4,” is recognized for its liver-soothing, spleen-strengthening, Qi-regulating, and depression-dispersing properties, building upon Xiaoyao Powder with modifications. Comprising Paeonia lactiflora Pall., Cyperus rotundus L., Smilax glabra Roxb., Angelica sinensis (Oliv.) Diels., Panax ginseng C.A.Mey., Gardenia jasminoides J. Ellis., Atractylodes macrocephala Koidz., Citrus reticulata Blanco., Glycyrrhiza glabra L., and Bupleurum chinense DC in specific ratios, KZD offers a holistic approach affecting multiple organs (heart, liver, spleen, lung, and kidney). Modern pharmacological perspectives identify sedative properties in eight of the herbs, cardiovascular benefits in ten, immune support in seven, anti-inflammatory and antibacterial effects in six, and antipyretic and analgesic actions in five (Jin et al., 2019; Li et al., 2022a, b, c, d; Li et al., 2019; Lu et al., 2022a, b; Yan et al., 2018). Enhancements over Xiaoyao Powder, such as the inclusion of aromatic compounds and tangerine peel for better liver and Qi regulation, gardenia for heat clearance and blood cooling, and ginseng for Qi invigoration and deficiency treatment, highlight KZD's superior efficacy. Historical and contemporary research underscores KZD's significant role in managing neurosis and gastrointestinal ailments, evidencing its therapeutic versatility and potential in depression treatment and gastrointestinal discomfort alleviation.

The intricate compositions of Traditional Chinese Medicine (TCM) pose a challenge in dissecting its multifaceted targets and fully elucidating the mechanisms underlying its antidepressant effects. Critical proteins within signaling pathways such as cAMP (Gao et al., 2022), MAPK (Lu et al., 2022a, b), BDNF, and mTOR (Zhang et al., 2024) are recognized for their pivotal roles in TCM's antidepressant pathways. These signaling cascades facilitate a range of downstream effects, including neuroprotection, angiogenesis, and enhanced synaptic plasticity, contributing to their antidepressant efficacy.

Diverging from conventional pharmacological approaches that focus on “single target, single drug” paradigms, network pharmacology offers a comprehensive and holistic perspective, mirroring the integrative nature of TCM (Guo et al., 2022; Wang et al., 2021a, b, c). The advent and advancement of high-throughput, multi-omics technologies have significantly bolstered the validation and application of network pharmacology, facilitating in-depth exploration of the action mechanisms of TCM formulations (Yu et al., 2021; Zhu et al., 2020).

This study aims to identify the primary components and investigate the potential antidepressant-like effects and mechanisms of Kaiyu Zhishen Decoction (KZD) through network pharmacology, complemented by empirical validation.