Breast cancer constitutes a significant contributor to cancer-related mortality among women (1), and data from China show that its incidence ranks second among cancers (2). The pathogenesis of breast cancer involves multiple mechanisms, among which emotional factors play a key role in the occurrence and progression of this disease (3). Previous studies, including systematic reviews (4), multicenter clinical studies (5), and Delphi study (6), have consistently identified Liver depression syndrome as the main clinical pattern of breast cancer. Liver depression syndrome is a general syndrome term which contains a series of syndrome subtypes centered on constrained Liver qi. Based on the common etiology, different syndrome subtypes can be divided at different stages of pathology (7).

In TCM theory, it is believed that the core pathogenesis of Liver depression syndrome is attributed to chronic emotional constraint and psychosocial stressors. Characteristic clinical manifestations encompass depression, sighing propensity, and irritability (8). In breast cancer, multiple etiological factors beyond emotional dysregulation can precipitate Liver depression. For example, breast cancer patients can suffer chronic emotional depression due to gender role stress (9). Meanwhile, modern lifestyles including lack of sleep (10), sedentary behavior (11) and high-fat diet (12) can also disrupt Liver function through multiple mechanisms. Thus, under the cumulative effect of these factors, persistent stagnation of Liver qi gradually disrupts the inter-organ coordination of the Liver, Spleen and Kidney, as well as the homeostasis of qi and blood circulation (13). This pathological state initiates a cascade of pathophysiological processes, such as qi stagnation, blood stasis, phlegm accumulation and toxin accumulation. These abnormalities accumulate in the mammary tissue, ultimately contributing to the oncogenesis of breast cancer.

While diagnostic criteria exist for subtype patterns like the Liver depression with qi stagnation and Liver depression with phlegm coagulation (7), standardized diagnostic parameters specific to breast cancer-associated Liver depression syndrome remain undefined. The standardization of syndrome diagnosis holds significant implications for TCM clinical practice and research. Establishing unified diagnostic criteria for Liver depression syndrome would not only enhance the precision of syndrome differentiation in breast cancer management but also facilitate the standardized application of TCM therapeutic approaches in breast cancer prevention and treatment. Moreover, such standardization would provide essential support for developing integrated TCM and Western medicine diagnostic frameworks and promote the international dissemination of research outcomes. Building on this, the current study systematically consolidates literature evidence and performs evidence-based medical evaluations to establish a scientific framework for developing standardized diagnostic criteria for Liver depression syndrome in the context of breast cancer.

The methods employed to identify relevant research articles were guided by the protocols outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Additionally, this study was meticulously reported in strict adherence to the PRISMA guidelines. This systematic review was prospectively registered on PROSPERO (Registration ID: CRD42024546784).

A total of 255 eligible literatures were screened, including eight expert consensus documents, 130 textbooks/monographs, 35 medical record files of renowned physicians, and 82 contemporary research articles. It was worth noting that due to the reporting of multiple subtypes of Liver depression syndrome in some literatures, thus, a total of 298 clinical entries were ultimately analyzed. The literature screening was shown in Figure 1.

Traditional Chinese Medicine demonstrates therapeutic potential in breast cancer, with studies indicating its efficacy in alleviating side effects and improving quality of life (17–19). While Liver depression syndrome is a key clinical syndrome in breast cancer pathogenesis, the lack of standardized diagnostic criteria has hindered scientific understanding and TCM intervention development. This study systematically synthesizes literature to outline its clinical characteristics, dominant symptoms, and tongue–pulse diagnostic indicators, facilitating precise syndrome characterization and supporting TCM oncology theory refinement. Our study indicates that breast cancer patients with Liver depression syndrome exhibit six main symptom clusters: breast-related abnormalities, emotional disturbances, Liver meridian pathway manifestations, chest-abdominal discomfort, menstrual irregularities, and bowel/bladder dysfunction. Emotional symptoms, such as depression, anger, vexation, often fluctuating alongside emotional states.

The results of this study indicate that Liver depression syndrome in breast cancer presents with a variety of tongue and pulse manifestations. Across all literature related to Liver depression syndrome, thin white fur and stringy pulse are the most frequently observed. Tongue and pulse are critical diagnostic parameters in TCM syndromes. Previous studies have established several criteria for Liver depression syndrome across various diseases, yet tongue manifestations are seldom mentioned. For instance, tongue signs were not included in the diagnostic criteria for Liver depression and Liver qi depression syndromes (20, 21), suggesting that experts consider tongue signs to lack specificity for these patterns. In the criteria for Liver depression syndrome, the tongue description “pale tongue with thin white fur” represents normal physiological findings (22). This may reflect the TCM theory that tongue coating reflects Stomach qi transformation, while Liver depression primarily disrupts qi movement without directly inducing dampness or heat accumulation, leading to subtle tongue coating changes and reduced diagnostic value. In contrast, pulse conditions play a crucial role in the diagnosis of Liver depression syndrome. The stringy pulse is the only consistent indicator across criteria, aligning with our literature review findings.

TCM deeply understands Liver depression syndrome, identifying various causes such as external pathogens, emotional stress, and phlegm accumulation that disrupt the flow of vital energy qi. In breast cancer, Liver depression is both a common pattern and a crucial factor. TCM believes breast tissue is connected to the Liver meridian system, and breast health depends on the Liver and Stomach working together. Chronic emotional suppression or sudden anger can cause Liver qi stagnation, impairing Spleen function and nutrient processing. Combined with a diet high in rich or fatty foods, this can lead to internal phlegm-dampness buildup. When these harmful elements gather in breast tissue, they create the conditions for cancer to develop. Besides, emotional factors play a dominant role in Liver regulation, and Liver depression is linked to tumorigenesis in multiple ways. The Liver meridian traverses the throat, and prolonged Liver depression can generate fire-toxin. This fire-toxin scorches body fluids into phlegm, contributing to thyroid cancer (referred to as “gall tumors” in TCM) (23). Additionally, Liver depression and repressed anger induce qi stagnation and blood stasis, which are the pathological mechanisms underlying liver cancer (24).

In TCM, a classical view holds that Liver depression is a key pathogenic factor in breast cancer oncogenesis (25). However, since Liver depression syndrome comprises multiple subtypes, it remains unclear whether all subtypes contribute to breast cancer development. This uncertainty warrants further investigation. These subtypes reflect the progression of Liver depression through distinct pathological stages. TCM emphasizes “transformation of pathogenesis”, indicating that syndromes are not static but can evolve as the disease progress. Literature and textbooks (26, 27) show that in the early stage of breast cancer, Liver depression with qi stagnation is the main syndrome. Without timely intervention, it may gradually evolve into Liver depression transforming into fire, followed by Liver depression with blood stasis and phlegm coagulation. Prolonged Liver depression can damage Spleen function, leading to Spleen deficiency. Therefore, Liver depression with qi stagnation serves as the pathological foundation, while other syndrome manifestations are results of pathological evolution. Each subtype is not independently pathogenic but is jointly triggered by the pathological chain of “qi stagnation–phlegm stasis–toxic accumulation–vital deficiency”.

In terms of treatment, TCM focuses on getting the body’s energy qi flowing smoothly again by regulating the Liver. A prime example is the classic TCM formula Chaihu Shugan San, which relieves Liver congestion and improves emotional well-being and quality of life (28–30). With modern technological advancements, we can investigate specific effector pathways and molecular targets associated with Liver depression syndrome in breast cancer using histological and omics techniques (31). Our goal is to uncover the syndrome’s microscopic and molecular signatures. Additionally, using our team’s established Liver depression syndrome breast cancer mouse model, we can assess the efficacy of TCM interventions on key signaling nodes. This will provide a solid basis for precisely targeting Liver depression syndrome in breast cancer therapy.

Depressive symptoms in breast cancer patients are a significant public health issue (32–34), with a 30.2% prevalence globally in 2023 (35). There are significant clinical and pathophysiological links between TCM’s Liver depression syndrome and Western-defined depression in these patients. Modern biomedical research recognizes chronic stress as fundamentally analogous to TCM’s “Liver constraint” (Liver qi stagnation), as shown by preclinical studies using chronic stress models to induce Liver depression syndrome (36–38). Chronic psychological stress activates the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, releasing substances that promote cancer progression (39) and impair immune surveillance (40), thereby increasing breast cancer susceptibility (41, 42). Additionally, experimental data show that chronic psychological stress accelerates mammary tumor growth and metastasis in mouse models, while the TCM formula Sini San counteracts these effects by reducing stress-induced aerobic glycolysis (43). The TCM pathomechanism of “qi stagnation” aligns with depression-associated dysregulation of the neuroendocrine-immune network. In TCM theory, the Liver regulates qi flow and emotions, and therapies that restore Liver qi dynamics likely exert multi-mechanistic effects: simultaneously normalizing qi circulation, alleviating emotional distress, and enhancing immune surveillance (44–46).

This study systematically maps the literature on Liver depression syndrome in breast cancer, but limitations exist. Most studies (56.1%) were Level V non-controlled, reflecting the current dominance of observational and case-based evidence in this field. Though valuable for clinical insights, their retrospective design and lack of control groups limit causal inference. Future research should focus on establishing standardized diagnostic criteria for Liver depression syndrome in breast cancer to enhance diagnostic accuracy and consistency. Utilizing advanced multi-omics technologies like metabolomics and spatial transcriptomics can help elucidate the syndrome’s biological mechanisms and identify key molecular events related to clinical depression. Integration of artificial intelligence (AI) and big data analytics will aid in developing objective biomarkers and early detection tools, advancing TCM syndrome standardization. Multicenter clinical trials are needed to validate the effects of Liver qi-regulating therapies on the tumor microenvironment and optimize herbal formulas. These efforts will promote the development of integrative TCM-Western treatment models to improve breast cancer prognosis.