Depression and anxiety disorders exhibit high comorbidity and share overlapping biological mechanisms, with more than 60 % of individuals with major depression suffering from anxiety disorders. A report from World Health Organization in 2017 showed that depression and anxiety affect staggering 280 million and 322 million people globally with non-fatal disease burden of 10 % and 4 % respectively. In addition, there are increasing evidence that depression is highly correlated with other illnesses and high risk of suicide (Blom et al., 2024; Yu et al., 2024). Genetic predisposition, combined with adverse early-life experiences such as childhood maltreatment (Opel et al., 2019; Rocha et al., 2015) and later-life stressors including childbirth and chronic stress, contribute to alterations in central neurotransmitter systems, ultimately leading to the development of depression. Psychotherapy and antidepressant medications are effective first-line depression treatments (Simon et al., 2024). Beyond that, acupuncture and botanical drugs are also used due to their fewer adverse reactions and even higher response efficiency (Xu et al., 2022; Zhai et al., 2015). However, approximately 50 %–80 % of patients have at least one relapse in their lifetime and experience various adverse reactions (Spindelegger et al., 2014; Rothmore, 2020; Eaton et al., 2008).

Microbiota-gut-brain (MGB) axis is a bidirectional communication network involving the gut microbiota, their metabolites, the gut, and the brain, mediated through neural, endocrine, and immune pathways (Cryan et al., 2019; Cryan and Dinan, 2012). Based on this, the blockbuster drug sodium oligomannate (GV971) was marketed to treat Alzheimer's disease (Wang et al., 2019). Similarly, the role of the MGB axis in depression has been widely recognized (Li et al., 2022). In brief, alterations in the gut microbial composition and metabolite profile in major depressive disorder contribute to intestinal barrier impairment and provoke local inflammatory responses. These changes facilitate the systemic translocation of gut-derived substances, thereby promoting peripheral and central inflammation. In addition, some bacterial and host metabolites can cross the blood-brain barrier and exacerbate depression by affecting the state of the hippocampus. Besides, the enteric nervous system, vagus nerve and hypothalamic-pituitary-adrenal axis also play the important roles in signal transmission of MGB axis (Liu et al., 2023).

Lipids are particularly enriched in the brain, constituting more than half of its dry weight and exhibiting a more diverse composition compared to other tissues. This unique lipid profile has been considered a potential biomarkers of brain disorders (Hussain et al., 2020). As a key regulator of lipid metabolism, gut microbiota significantly affects lipid metabolism in both peripheral tissues and the central nervous system (Luo et al., 2024). Glycerophospholipid metabolism, as an important part of lipid metabolism, has been increasingly linked to MGB axis-mediated pathogenesis of depression over the past three years. By integrating multi-omics data, Tian et al. found glycerophospholipid metabolism is the vital link between gut microbiota and hippocampus in the onset of mice depressive-like behaviors (Tian et al., 2022). Besides, in a cynomolgus monkey model of depression, it was found that modulation of peripheral and central glycerophospholipid metabolism, gut microbiome may participate in improving depressive-like behaviors (Zheng et al., 2021). Therefore, targeting abnormalities in peripheral and central glycerophospholipid metabolism may offer a novel therapeutic strategy for depression.

Hypericum perforatum L., also known as St. John's wort, is widely used for the treatment of sleeping disorders, anxiety and mild depression in Europe and the United States from the 1990s. For the equivalent efficacy and fewer side effects than chemical medicines, it is perceived as a safe alternative to synthetic drugs (Ng et al., 2017). As a primary active dianthrone compound, hypericin exhibits potent antidepressant effects through multiple mechanisms, including modulation of monoamine receptors, inhibition of monoamine oxidase, prevention of amine reuptake, and attenuation of neuroinflammatory responses in the hippocampus (Jolodar et al., 2021; Peng et al., 2023). More cutting-edge researches showed that hypericin ameliorates depression-like behaviors by mediating m6A modification, NLRP3 inflammasome activation and connexin 43-based gap junctions (Zhai et al., 2022; Lei et al., 2023; Wang et al., 2023).

Although Hou et al. have shown that Cuscutae semen, containing hypericin, alleviates chronic unpredictable stress -induced depression-like behaviors in mice via the gut microbiota-neuroinflammation axis, direct evidence supporting that hypericin itself ameliorates depression through the MGB axis remains lacking to date (Hou et al., 2023). In addition, given the low solubility and poor bioavailability of hypericin, it is reasonable to hypothesize that hypericin may alleviate depression via the MGB axis. To further elucidate the antidepressant mechanism of hypericin, this study employed a chronic restraint stress (CRS) mouse model to investigate whether hypericin exerts antidepressant effects through the MGB axis and to explore its underlying signaling pathways. These findings may contribute to the development of preventive strategies and interventions for depression.