Background: Despite the critical progress of non-small cell lung cancer (NSCLC) therapeutic approaches, the clinical outcomes remain considerably poor. The requirement of developing novel therapeutic interventions is still urgent. In this study, we showed for the first time that diosbulbin C, a natural diterpene lactone component extracted from traditional Chinese medicine Dioscorea bulbifera L., possesses high anticancer activity in NSCLC. Methods: A549 and NCI-H1299 cells were used. The inhibitory effects of the diosbulbin C on NSCLC cell proliferation were evaluated using cytotoxicity, clone formation, EdU assay, and flow cytometry. Network pharmacology methods were used to explore the targets through which the diosbulbin C inhibited NSCLC cell proliferation. Molecular docking, qRT-PCR, and western blotting were used to validate the molecular targets and regulated molecules of diosbulbin C in NSCLC. Results: Diosbulbin C treatment in NSCLC cells results in a remarkable reduction in cell proliferation and induces significant G0/G1 phase cell cycle arrest. AKT1, DHFR, and TYMS were identified as the potential targets of diosbulbin C. Diosbulbin C may inhibit NSCLC cell proliferation by downregulating the expression/activation of AKT, DHFR, and TYMS. In addition, diosbulbin C was predicted to exhibit high drug-likeness properties with good water solubility and intestinal absorption, highlighting its potential value in the discovery and development of anti-lung cancer drugs. Conclusions: Diosbulbin C induces cell cycle arrest and inhibits the proliferation of NSCLC cells, possibly by downregulating the expression/activation of AKT, DHFR, and TYMS.

The disruption of zinc (Zn) homeostasis has been implicated in cancer development and progression through various signaling pathways. Maintaining intracellular zinc balance is crucial in the context of cancer. Human cells rely on two families of transmembrane transporters, SLC30A/ZNT and SLC39A/ZIP, to coordinate zinc homeostasis. While some ZNTs and ZIPs have been linked to cancer progression, limited information is available regarding the expression patterns of zinc homeostasis-related genes and their potential roles in predicting prognosis and developing therapeutic strategies for specific cancers. In this study, a systematic analysis was conducted to examine the expression of all genes from the SLC30A and SLC39A families at both mRNA and protein levels across different cancers. As a result, three SLC39A genes (SLC39A1, SLC39A4, and SLC39A8) were found to be significantly dysregulated in specific cancers, including cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), liver hepatocellular carcinoma (LIHC), pancreatic adenocarcinoma (PAAD), and kidney renal papillary cell carcinoma (KIRP). Moreover, the dysregulation of these genes was tightly associated with the prognosis of patients with those cancers. Furthermore, we found that the gene SLC39A8 exhibited the lowest mutation frequency in KIRP, whereas mutations in SLC39A4 were found to significantly impact overall survival (OS), disease-free (DF), and progress-free survival (PFS) in cancer patients, particularly in those with PAAD. Additionally, immune infiltration analysis revealed that SLC39A1, SLC39A4, and SLC39A8 may function as immune regulators in cancers. This provides new insights into understanding the complex relationship between zinc homeostasis and cancer progression.

Observational studies provide evidence of correlations between cancer and the immune system. Previous research has established associations between immune traits and the propensity for developing certain cancers. However, a systematic exploration of these connections remains largely uncharted. Therefore, further investigation is needed to examine the causal association between cancer and immune cell traits using Mendelian randomization (MR) approach. We identified genetic instruments for breast cancer (BC), lung cancer (LC), endometrial cancer (EC), ovarian cancer (OC), prostate cancer (PC), and their subtype cancers to investigate their potential causal impact on immune traits. Data on cancer and immune cell traits were obtained from the IEU Open GWAS project. To assess whether these five cancer types and subtype cancers have a causal association with immune cell traits, we conducted two-sample MR analyses. Additionally, we conducted bidirectional MR analyses to examine the direction of causal relationships and adjusted for potentially related pleiotropy through multivariable MR analysis. We have identified several causal relationships between different types of cancer and immune traits. We found that breast cancer may influence 49 immune cell traits, endometrial cancer may influence 38, lung cancer may influence 25, ovarian cancer may influence 19, and prostate cancer may influence 28. Among these, breast cancer and lung cancer were associated with four common immune traits: CD25 on IgD⁻ CD38^dim, CD25 on sw mem, CD24 on IgD⁻ CD38⁻, and CD25 on IgD⁻ CD38⁻. Lung cancer and prostate cancer shared four immune traits: CD25 on IgD⁺ CD24⁺, CD25 on IgD⁺ CD38⁻, CD66b on CD66b⁺⁺ myeloid cell, DN (CD4⁻CD8⁻) AC. Endometrial cancer and ovarian cancer shared two immune traits: TD DN (CD4⁻CD8⁻) %DN, EM DN (CD4⁻CD8⁻) %DN. Breast cancer and endometrial cancer shared one immune trait: CD20 on IgD⁻ CD38^dim. Endometrial cancer and prostate cancer shared one immune trait: CCR2 on myeloid DC. Lastly, breast cancer, lung cancer, and prostate cancer shared one immune trait: CD25 on CD24⁺ CD27⁺. Additionally, we identified specific immune traits that may serve as protective or risk factors for cancers. We found 14 immune traits may influence breast cancer, 9 immune traits may influence endometrial cancer, 22 immune traits may influence lung cancer, 9 immune traits may influence ovarian cancer, and 14 immune traits may influence prostate cancer. Among these, breast cancer and prostate cancer shared three immune traits: HLA DR⁺⁺ monocyte %monocyte, HLA DR on plasmacytoid DC, and HLA DR on DC. Lung cancer and ovarian cancer shared one immune trait: CD62L⁻ monocyte %monocyte. Prostate cancer and endometrial cancer shared one immune trait: HLA DR on CD33^dim HLA DR ⁺ CD11b⁺. Lastly, ovarian cancer and prostate cancer shared one immune trait: CD3 on resting Treg. Our MR study suggests a potential relationship between immune traits and cancers, particularly highlighting 14 immune traits that are simultaneously influenced by two or three of five cancer types, while also indicating that 6 immune traits may simultaneously contribute to the development of two of the cancers. This elucidation enables us to reveal a significant involvement of immune traits in cancer progression, providing critical insights into how immune traits affect cancer susceptibility.