Pyrazoloacridine

Lung squamous cell carcinoma (LUSC) is a subtype of lung cancer with a poor prognosis and limited treatment options. Previous studies show that some components of the cholinergic pathway may play important roles in the tumorigenesis of lung cancer, including LUSC.

The purpose of this study is to investigate the involvement of cholinergic genes in immune infiltration in LUSC, and identify the key genes in the pathway and analyze their potential as targets for LUSC treatment and novel drugs.

We first screened the cholinergic genes associated with immune infiltration in LUSC based on transcriptomic samples and explored the correlation between the key genes and immune infiltrating cells and immune pathways. Then, we assessed the effect of immunotherapeutic response in the high and low-expression groups of key genes in vitro. And finally, we screened potential drugs for the treatment of LUSC.

We found that the expression of CHRNA6, the gene encoding the α6 subunit of nicotinic acetylcholine receptors (nAChR), was significantly correlated with the proportion of immune infiltrating cells in LUSC, and the high expression level of the gene was associated with poor prognosis of the disease. Also, the proportion of Tregs, M1 macrophages, and resting mast cells was correlated with the expression of CHRNA6. In addition, LUSC patients with higher CHRNA6 expression levels had better immunotherapy responses. Furthermore, we found that the drugs, i.e., adavosertib, varbulin and pyrazoloacridine, had a strong affinity with CHRNA6, with adavosertib binding most stably with the protein.

CHRNA6 may be associated with immune infiltration in LUSC and affects patient prognosis and immunotherapeutic response by regulating immune cells and immune pathways. In addition, adavosertib may be a potential drug for the treatment of LUSC.

Lipid metabolism is crucial to tumor growth and immune microenvironment as well as drug sensitivity in glioma. Identifying prognostic indicators of glioma and elucidating the mechanisms of glioma progression are critical for improving the prognosis of glioma patients. In this study, we investigated the role and prognostic value of metabolism-related genes in glioma by integrative analysis of datasets from GEO, CGGA, and TCGA. Based on clinical data and transcriptome data, we found that the expression pattern of three major pathways related to lipid metabolism is fatty acid^high-phospholipid^high-triglyceride^low, which is associated with better prognosis and immune infiltration. The genes involved in these three pathways were used to generate a prognostic model, which showed high stability and efficiency in the test set and validation set. The spatial transcriptome of glioma patients revealed that the microenvironment of the regions with high expression of risk genes CAV1 and SCD is in a state of hypoxia, EMT, and cell cycle arrest, and thus can be used as markers of metabolic reprogramming in the tumor microenvironment. In the high-risk group, M0 macrophages and M1 macrophages were significantly enriched, and the risk score was significantly correlated with gene mutation and methylation of risk genes. We further performed drug sensitivity screening corresponding to different risk genes. This study provided novel insights into the differential immune microenvironment with different expression patterns of metablism-related genes and highlighted the spatial and temporal synergy of tumor progression and metabolic reprogramming.