Exploring The Genetic Causal Relationship, Pathogenic Mechanisms, And TCM Interventions For LUAD And MDD
Apr 24, 2025
3 Discussion
3.1 Genetic Causal Effect and Potential Pathogenic Mechanisms Between LUAD and MDD
The phrase "all qi stagnation and depression are related to the lung" originates from Huangdi Neijing: Suwen: Essential Theories of the Celestial Truth [16]. Here, "膹" (péng) implies fullness or obstruction, while "郁" (yù) refers to stagnation. Therefore, "膹郁" describes a state of qi stagnation and obstruction. This theory suggests that pathological states of qi stagnation and depression are closely related to the lung.
The results of this study's MR analysis support that LUAD may slightly increase the risk of MDD, with robust causal effect findings, further validating this traditional Chinese medicine theory. These results provide preliminary evidence for managing the mental health of LUAD patients, emphasizing the need for psychological interventions. However, further biological experiments and larger genetic datasets are needed to confirm the causal mechanisms.
TCM Herbal Cistanche Formula For LUAD
LUAD may promote the onset of MDD by interfering with neural signal transmission through the cholinergic signaling pathway. This study identified 120 LUAD-related IVNGs. GO and KEGG functional enrichment analyses showed that the biological processes, cellular components, and molecular functions enriched by IVNGs were closely related to neurotransmission and neural regulation. KEGG pathway enrichment analysis revealed that the cholinergic signaling pathway (hsa04725) was the only significantly enriched pathway. This pathway is closely related to acetylcholine-mediated neurotransmitter signaling and is widely involved in signal regulation in the central and peripheral nervous systems.
Studies have found that in lung specimens resected from LUAD patients, the density of sympathetic nerve fibers is higher in peri-tumoral regions, while parasympathetic nerve fibers are mainly located within the tumor bed [17]. One of the main biological causes of MDD is neurotransmitter dysfunction, particularly involving monoamine neurotransmitters (e.g., dopamine, norepinephrine, and serotonin) and gamma-aminobutyric acid (GABA), which play crucial roles in this process [18–20].
Additionally, data show that comprehensive inhibition of sympathetic nervous activity may reduce the risk of primary lung cancer in smokers and nicotine addicts [21]. Other research has demonstrated a significant association between nicotine dependence and MDD [22–25]. Based on this, it is hypothesized that the physiological response to nicotine may serve as a common pathogenic mechanism for LUAD and MDD. Nicotine may even play a role, through its effects on the nervous system, in the process by which LUAD promotes the development of MDD.
Further analysis revealed that the neurobiological link between LUAD and MDD also involves transporter and ion channel activity, with a complex and interdependent relationship with MDD. Studies have shown that serotonin (5-hydroxytryptamine, 5-HT) transporter expression and function may be impaired in MDD patients, reducing serotonin availability and affecting mood states [18,26]. Similarly, ion channel dysfunction can trigger abnormal neuronal discharges, thereby affecting brain functional connectivity and leading to depressive symptoms [18].
The interaction between ion channel activity and transporter function plays a regulatory role. Neuronal depolarization may enhance transporter activity, promoting neurotransmitter reuptake and regulating synaptic transmission [18].
A-radar chart of distribution of four qi of traditional Chinese medicines; B-radar chart of distribution of five flavors of traditional Chinese medicines; Cradar chart of distribution of meridians of traditional Chinese medicines; D-pie chart of efficacy distribution of traditional Chinese medicines; E-"IVNGcomponent-traditional Chinese medicine" mapping network diagram (orange rhombus represents IVNGs, purple arrows represent components, and blue rectangles represent traditional Chinese medicines).
Fig. 7 Statistical analysis results of traditional Chinese medicines and mapping network diagram of "IVNG-componenttraditional Chinese medicine"
Table 5 Recognition results of similar classic formulas
| Similar Formula | Herbal Ingredients | Source of Formula | Similarity (%) |
|---|---|---|---|
| Ma Huang-based formulas | Ma Huang, Zhi Zi, Yi Yi Ren, Gan Cao | Jin Kui Yao Lue | 11.11% |
| Ma Huang Tang | Ma Huang, Gui Zhi, Xing Ren, Gan Cao | Shang Han Lun | 5.88% |
| Huang Lian Jie Du Tang | Huang Lian, Huang Qin, Huang Bai, Zhi Zi | Wai Tai Mi Yao | 5.56% |
| Wu Wei Xiao Du Yin | Jin Yin Hua, Pu Gong Ying, Ye Ju Hua, Zi Hua Di Ding, Tian Kui | Yi Fang Ji Jie | 5.56% |
| Wei Jing Tang | Lu Gen, Yi Yi Ren, Tao Ren, Dong Gua Zi | Jin Kui Yao Lue | 5.56% |
| Ji Chuan Jian | Rou Cong Rong, Dang Gui, Niu Xi, Ze Xie, Sheng Ma, Zhi Ke | Jing Yue Quan Shu | 5.56% |
| Hua Gan Jian | Chuan Lian Zi, Bai Shao, Zhi Ke, Gan Cao, Chen Pi | Yi Zong Jin Jian | 5.56% |
| Sang Xing Tang | Sang Ye, Xing Ren, Sha Shen, Bei Mu, Dan Dou Chi, Zhi Zi, Li Pi | Wen Bing Tiao Bian | 5.26% |
| Qing Ying Tang | Shui Niu Jiao, Sheng Di, Xuan Shen, Mai Dong, Jin Yin Hua, Lian Qiao, Huang Lian, Zhu Ye, Dan Shen | Wen Bing Tiao Bian | 5.26% |
| Xue Fu Zhu Yu Tang | Tao Ren, Hong Hua, Sheng Di, Dang Gui, Chi Shao, Chuan Xiong, Chai Hu, Zhi Ke, Jie Geng, Niu Xi, Gan Cao | Yi Lin Gai Cuo | 5.26% |
| Bai He Gu Jin Tang | Bai He, Sheng Di, Shu Di, Mai Dong, Xuan Shen, Bei Mu, Jie Geng, Dang Gui, Bai Shao, Gan Cao | Yi Zong Jin Jian | 4.76% |
| Wu Mei Wan | Wu Mei, Xi Xin, Huang Lian, Huang Bai, Fu Zi, Gui Zhi, Gan Jiang, Ren Shen, Dang Gui, Mi Zhi | Shang Han Lun | 4.76% |
| Ban Xia Hou Po Tang | Ban Xia, Hou Po, Fu Ling, Sheng Jiang, Su Ye | Jin Kui Yao Lue | 4.76% |
| Shen Ling Bai Zhu San | Ren Shen, Bai Zhu, Fu Ling, Shan Yao, Lian Zi, Bai Bian Dou, Yi Yi Ren, Sha Ren, Jie Geng, Gan Cao | Tai Ping Hui Min He Ji Ju Fang | 4.76% |
| Xiao Yao San | Chai Hu, Dang Gui, Bai Shao, Bai Zhu, Fu Ling, Zhi Gan Cao | Tai Ping Hui Min He Ji Ju Fang | 4.76% |
Note: The column "Similarity (%)" indicates the similarity between the identified formula and the classic formula.
3.2 Interaction Between Cholinergic Signaling Pathway and Other Neurotransmitter Systems in MDD
The cholinergic signaling pathway interacts with other neurotransmitter systems, which may play a critical role in regulating mood and behavior, and is a key factor in the pathogenesis of MDD [27]. Clinical studies have shown that increased central acetylcholine levels are associated with worsening depressive symptoms [28]. Moreover, changes in the activity of cholinergic neurons in the prefrontal cortex, a region closely related to emotional regulation, may directly affect the manifestation of MDD symptoms [29]. LUAD may promote the occurrence and progression of MDD through the interaction of multiple mechanisms, including neurotransmitter regulation, transporter activity, and ion channel function. This provides a new perspective for understanding the potential causal relationship between the two conditions.
3.2 Potential Traditional Chinese Medicine (TCM) Interventions for LUAD
Academician Tong Xiaolin's "State-Targeted Medicine" theory integrates modern precision medicine with the traditional Chinese concept of syndrome differentiation and treatment [5]. Inspired by this theory and combined with the "IVNGs-compounds-TCM" innovative therapeutic approach, this study explores the principles, methods, and formulas for treating LUAD.
The MR analysis results suggest that LUAD may contribute to the onset of MDD, a finding consistent with the TCM etiology and pathogenesis of LUAD. LUAD falls under the category of "Yu Zheng" (depressive syndrome) in TCM. The lung governs qi and respiration, and LUAD disrupts the lung's dispersing and descending functions, causing qi stagnation and emotional depression. Prolonged qi stagnation can generate internal heat due to stagnation. Additionally, as the lung connects to all vessels, cancer obstructs the flow of qi, blood, and body fluids, leading to stagnation of blood and phlegm. This aggravates emotional disturbances, while cancer toxins, blood stasis, phlegm, and heat further deplete qi, blood, and yin-yang, resulting in mental distress and persistent sorrow.
Hence, the TCM pathogenesis of LUAD involves intertwined factors of toxins, stasis, phlegm, heat, and stagnation. Over time, these factors damage the body's vital qi, leading to deficiencies in qi, blood, yin, and yang. As stated in Huangdi Neijing: Ling Shu: Ben Zang Pian, "The five organs store the spirit, blood, qi, soul, and will" [30]. When the organs are deprived of nourishment, the body weakens, and the spirit diminishes, leading to unresolved depression. This condition is characterized by a mix of deficiency and excess, cold and heat. Consequently, LUAD can be classified into "deficiency" and "excess" states. Corresponding "targeted syndromes, methods, formulas, and medicines" should emphasize both attacking and supplementing, with the dual goals of eliminating pathogenic factors and strengthening the body's resistance.
TCM-Based Classification and Treatment of LUAD
Based on the TCM predictions and efficacy analysis, the "excess" state of LUAD can be divided into the following syndromes:
Toxin (Heat) Congestion Syndrome
Blood Stasis Syndrome
Phlegm Accumulation Syndrome
Qi Stagnation Syndrome
The "deficiency" state corresponds to the following syndromes:
Qi Deficiency Syndrome
Blood Deficiency Syndrome
Yin Deficiency Syndrome
Yang Deficiency Syndrome
Treatment methods are established according to the specific syndrome. The corresponding "targeted methods" include:
Clearing heat and detoxifying
Purging fire and relieving restlessness
Activating blood circulation and resolving stasis
Resolving phlegm and draining dampness
Regulating qi and relieving stagnation
Tonifying qi and benefiting the middle
Nourishing and replenishing blood
Nourishing yin and generating fluids
Warming and tonifying yang
The predicted TCM herbs are matched to these targeted methods based on their efficacy. These predictions are further linked to the compounds and IVNGs associated with the herbs, forming a preliminary "State-Syndrome-Method-Formula-Medicine-Target" network diagram for LUAD treatment (Figure 8).
Fig. 8 "Target status-target evidence-target method-target drug-target" network constructed based on "status-target" medical theory
Clustering Analysis of High-Frequency Potential Chinese Medicinal Herbs
This study conducted clustering analysis of high-frequency potential medicinal herbs, categorizing them into five groups:
Group 1: Herbs that clear heat, resolve phlegm, and activate blood circulation. These herbs alleviate heat stagnation, dissolve phlegm accumulation, and remove blood stasis, promoting smooth lung qi and emotional regulation.
Group 2: Herbs that nourish the liver and kidney, dispel cold, relieve pain, and open lung meridians. These herbs harmonize the lung and kidney, nourish the spirit, and regulate qi, resulting in vitality and emotional stability.
Group 3: Herbs that tonify qi, consolidate the lung, and generate fluids to strengthen the body. They also clear the liver, benefit the gallbladder, activate blood circulation, and detoxify, harmonizing liver qi and unblocking lung qi, ultimately leading to emotional relief.
Group 4: Herbs that tonify the kidney and reinforce yang, addressing congenital deficiencies. These herbs also resolve phlegm, promote digestion, disperse masses, and activate blood circulation. The combination of attacking and reinforcing restores both physical and mental vitality.
Group 5: Herbs that nourish yin and yang, enrich essence, nourish blood, detoxify, and dissolve accumulation. These herbs address complex syndromes involving both cold and heat, deficiency and excess, replenishing essence and harmonizing qi.
Characteristics of Predicted TCM Herbs
Statistical analysis revealed that the four natures of the predicted herbs are predominantly warm, followed by neutral and cold. This aligns with the complex cold-heat pathology of LUAD. The five flavors are mainly sweet, followed by bitter and pungent. In Jin Kui Yao Lue: The First Chapter of Visceral Channels it is said: "For liver diseases, use sour to supplement, bitter to reinforce, and sweet to harmonize" [31].
Sweet flavor: Has tonifying, harmonizing, and calming effects, supplementing liver blood and enhancing the spleen and stomach to generate qi and blood. With adequate yin and blood, the liver achieves harmony, easing liver qi.
Bitter flavor: Reinforces heart fire, which supports liver wood (the child-mother relationship). Bitter herbs also purge fire while preserving yin to prevent excessive liver fire from damaging yin.
Pungent flavor: Dispels cold phlegm, promotes blood circulation, unblocks qi, and regulates emotions.
The meridian tropism of the herbs focuses primarily on the liver, followed by the lung, with secondary effects on the spleen, stomach, kidney, and heart. LUAD primarily affects the lung and liver, but chronic conditions can extend to other organs. Herbs targeting the liver and lung meridians can directly address the disease location for effective treatment.
High-Frequency Herbs and Classic Prescriptions
Among the 15 most frequently predicted herbs, some overlap with classic prescriptions, such as Ma Huang, Zhi Zi, Yi Yi Ren, Pu Gong Ying, and Rou Cong Rong:
Ma Huang: Induces sweating, releases the exterior, and promotes lung qi. Common formulas include Ma Xing Yi Gan Tang, Ma Huang Xi Xin Fu Zi Tang, Ma Xing Shi Gan Tang, and Ma Huang Tang. These formulas can be referenced for LUAD syndromes involving obstructed lung qi and internal phlegm.
Zhi Zi: Clears heat, relieves restlessness, cools the blood, detoxifies, and alleviates damp-heat. Representative formulas include Huang Lian Jie Du Tang, Hua Gan Jian, Sang Xing Tang, and Huai Hua San. These can treat syndromes such as heat disturbing the heart, liver qi stagnation transforming into fire, and lung dryness with obstructed qi.
Yi Yi Ren: Dispels pus and detoxifies while strengthening the spleen and draining dampness. In Ma Xing Yi Gan Tang, it is combined with Ma Huang and Xing Ren to remove damp toxin and promote lung qi circulation, suitable for treating LUAD with internal dampness-toxin accumulation.
Pu Gong Ying: Targets the liver, clearing heat, detoxifying, dispersing masses, and alleviating swelling. It is effective for liver heat and toxin stagnation and is included in formulas like Wu Wei Xiao Du Yin.
Rou Cong Rong: Tonifies kidney yang, nourishes essence and blood, and lubricates intestines. It reinforces lung qi circulation and is useful for LUAD with kidney yang deficiency and insufficient essence. Representative formula: Ji Chuan Jian.
Differences Between Predicted Herbs and Classic Prescriptions
Despite overlapping with some classic prescriptions, the predicted herbs differ significantly in composition from traditional LUAD prescriptions. This may be due to:
Differences in drug sources and historical contexts: Modern herbal studies include broader sources, such as newly discovered plants, animals, and minerals, while classic prescriptions reflect the limited resources of their time. For example, herbs like chicory, jujube, and spirulina, which are absent in classic formulas, are now widely recognized.
Differences in research methods and focus: This study integrates bioinformatics and global databases to explore molecular mechanisms and potential therapies, while classic prescriptions are based on traditional TCM theories and clinical experience, emphasizing holistic treatment.
Evolution of disease spectra: Modern diseases and treatment needs differ from ancient contexts. Classic prescriptions target common ancient illnesses, whereas modern TCM predictions incorporate contemporary disease characteristics and treatment demands.
Advancing the Innovation of TCM
To ensure the innovation and development of TCM, modern research must integrate TCM's foundational theories with new knowledge. Although the predicted herbs have molecular evidence supporting their efficacy, they should not be applied blindly without guidance from TCM principles. Clinical practitioners should adhere to TCM syndrome differentiation and adjust herbal combinations and dosages as needed to enhance precision, safety, and effectiveness in treatment.
4 Conclusion and Future Outlook
This study explored the genetic causal relationship between LUAD (lung adenocarcinoma) and MDD (major depressive disorder) and their potential pathogenic mechanisms. MR analysis revealed that LUAD may slightly increase the risk of MDD through certain genetic mechanisms, supporting the existence of a potential genetic link between the two conditions. The study further uncovered that LUAD could influence the occurrence of MDD through multiple mechanisms, including neural signal transmission, the cholinergic signaling pathway, and neural regulation. Additionally, based on the "State-Targeted Medicine" theory and predicted potential Chinese medicinal interventions, this study analyzed the TCM principles, methods, and formulas for treating LUAD, providing new ideas and methods for clinical TCM applications.
Looking ahead, large-scale genetic data and biological experiments are needed to further verify the causal relationship between LUAD and MDD and to deeply investigate the molecular mechanisms underlying their interaction. Moreover, integrating precision medicine tailored to individual differences, there is a need to develop more effective treatment strategies, particularly in combining psychological health interventions with malignant tumor treatments.
The predicted Chinese medicinal herbs in this study exhibit significant innovation. Future research should validate these predictions through evidence-based medicine and clinical trials to confirm the efficacy and feasibility of the proposed interventions in LUAD treatment.
References
Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin, 2024, 74(3): 229-263.
Zeilinger E L, Oppenauer C, Knefel M, et al. Prevalence of anxiety and depression in people with different types of cancer or haematologic malignancies: A cross-sectional study [J]. Epidemiol Psychiatr Sci, 2022, 31: e74.
Shi J J, Wen W Q, Long J R, et al. Genetic correlation and causal associations between psychiatric disorders and lung cancer risk [J]. J Affect Disord, 2024, 356: 647-656.
Lee M J, Huang C W, Lee C P, et al. Investigation of anxiety and depressive disorders and psychiatric medication use before and after cancer diagnosis [J]. Psychooncology, 2021, 30(6): 919-927.
Tong Xiaolin, He Lisha, Zhao Linhua. On the "State-Targeted Causal" strategy for clinical TCM syndrome differentiation and treatment [J]. Journal of Traditional Chinese Medicine, 2015, 56(17): 1441-1444.
Dönertaş H M, Fabian D K, Valenzuela M F, et al. Common genetic associations between age-related diseases [J]. Nat Aging, 2021, 1(4): 400-412.
Lawlor D A, Harbord R M, Sterne J A C, et al. Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology [J]. Stat Med, 2008, 27(8): 1133-1163.
Purcell S, Neale B, Todd-Brown K, et al. PLINK: A tool set for whole-genome association and population-based linkage analyses [J]. Am J Hum Genet, 2007, 81(3): 559-575.
Consortium W T C C. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J]. Nature, 2007, 447(7145): 661-678.
Khera A V, Chaffin M, Aragam K G, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations [J]. Nat Genet, 2018, 50(9): 1219-1224.
Yu G C, Wang L G, Han Y Y, et al. clusterProfiler: An R package for comparing biological themes among gene clusters [J]. OMICS, 2012, 16(5): 284-287.
Tian S S, Zhang J B, Yuan S L, et al. Exploring pharmacological active ingredients of traditional Chinese medicine by pharmacotranscriptomic map in ITCM [J]. Brief Bioinform, 2023, 24(2): bbad027.
Xu Fan, Wang Yunlai, Peng Daiyin. Current research status of TCM components and related considerations [J]. World Science and Technology-Modernization of Traditional Chinese Medicine, 2018, 20(2): 163-168.
Jia Yansha, Zhang Xuejia, Tan Ninghua. Advances in research on the temporal and spatial specificity of chemical components in Chinese medicinal materials [J]. Chinese Herbal Medicine, 2024, 55(24): 8580-8588.
