Background Aristolochic Acid I (AAI) is a potent nephrotoxin and Group 1 carcinogen. Despite stringent regulatory restrictions, AAI-containing herbal remedies are still sporadically used to treat respiratory symptoms, presenting a previously underappreciated exposure risk for patients with lung adenocarcinoma (LUAD). However, the specific tumor-promoting effects of AAI on preexisting LUAD remain to be fully elucidated. Methods In this study, we integrated network toxicology, TCGA transcriptomic analysis, and molecular docking to identify core oncogenic networks potentially affected by AAI. The associated pro-tumor phenotypes and transcriptional regulatory abnormalities were subsequently investigated through a series of in vitro and in vivo experiments. Results Network analysis and TCGA data mining identified a cluster of seven hub genes—including ERBB2, SERPINE1, CCNA2, and CHEK1—that are crucial to LUAD progression and significantly associated with poor clinical prognosis. Molecular docking simulations suggested potential binding affinities between AAI and these target proteins. Functional assays demonstrated that acute AAI exposure significantly accelerated the proliferation, migration, and invasion of LUAD cell lines (PC9 and NCI-H1299) in vitro, while promoting macroscopic xenograft tumor growth in vivo. The RT-qPCR and WB results showed that AAI exposure was accompanied by an increase in the expression of core genes. Conclusion Our findings suggest that, beyond its established chronic mutagenic toxicity, AAI may act as a potent tumor promoter in LUAD. By potentially influencing key oncogenic networks, AAI accelerates the malignant progression of LUAD, underscoring the severe clinical hazards of AAI exposure in patients with preexisting lung malignancies.
Linchuan Mo, Fenglei Yu, Muyun Peng et al.· Frontiers in Pharmacology· 0 citations
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer incidence and mortality worldwide. In recent years, immune checkpoint inhibitors (ICIs), particularly those targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis, have significantly improved survival outcomes in a subset of patients. However, the magnitude and durability of clinical benefit vary considerably according to PD-L1 expression, treatment setting, histological subtype, oncogenic driver status, and whether ICIs are administered as monotherapy or in combination regimens. A substantial proportion of patients therefore exhibit either primary resistance or acquired resistance after an initial response. This review systematically summarizes the key mechanisms underlying immune resistance in lung cancer. These include defects in antigen presentation, such as abnormalities in major histocompatibility complex class I (MHC-I), transporter associated with antigen processing 2 (TAP2), and β2-microglobulin (B2M), as well as dysregulation of the interferon-γ/Janus kinase-signal transducer and activator of transcription (IFN-γ/JAK-STAT) signaling pathway. Tumors frequently exhibit an immune-excluded or ‘cold’ phenotype, which further limits immune recognition and reduces responsiveness to immunotherapy. This review summarizes immune resistance in NSCLC through a framework that distinguishes primary resistance from acquired resistance. Primary resistance reflects failure of immune activation at treatment initiation, usually due to pre-existing tumor-intrinsic or microenvironmental barriers, including impaired antigen presentation, defective IFN-γ/JAK-STAT signaling, low tumor immunogenicity, immune-cold or immune-excluded phenotypes, and suppressive TME states. In contrast, acquired resistance reflects adaptive tumor and immune ecosystem evolution under therapeutic pressure, leading to neoantigen loss, HLA or B2M alterations, compensatory checkpoint activation, progressive T cell exhaustion, TME remodeling, and epigenetic stabilization of immune escape. We further discuss mechanism-based biomarkers, translational correlates, and rational therapeutic strategies for overcoming resistance.
Bo Yuan, Wenzhi Deng, Juan Luo et al.· Frontiers in Immunology· 0 citations