Current Topics in Medicinal Chemistry - Volume 26, Issue 3, 2026

Routine synthetic chemo-drugs for the treatment of glioma exhibit limited blood-brain barrier (BBB) permeation and unavoidable serious neuronal toxicity with substandard treatment outcomes, which necessitates the exploration of novel, efficacious yet healthy tissue-friendly entities having the desired physicochemical characteristics with effective anticancer potential.

ADMET analysis to investigate drug-likeness and toxicity profile of alpha-terpineol, followed by characterization of selected proteins. In silico studies, such as molecular docking and molecular simulation studies, were employed. Further, to validate the in silico results, an in vitro MTT assay and an in-vitro antioxidant study were carried out.

ADMET analysis showed promising results. Alpha-terpineol docked preferentially with selected glioma proliferation proteins, having a good docking score (>8). Reasonable antioxidant and cytotoxicity activity (IC50 18.3±1.1 µg/ml) was observed from DPPH and MTT assays .

The present study confirmed the potential anti-inflammatory, antioxidant, and anticancer effects of AT, which were further supported by in vitro study results. ADME analysis showed favourable drug-likeness of AT with desirable BBB permeation characteristics. AT was found to be potentially toxic to C6 glioma cells, whereas negligibly toxic to healthy neuronal cells.

The outcomes of the study provide supportive evidence to proceed with further in vivo testing of AT in glioma models to establish it as a potent, efficacious anticancer drug.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. M1 macrophages exhibit dual roles in the tumor microenvironment (TME), but the specific mechanisms underlying their involvement in HCC remain unclear.

M1-polarized macrophages were differentiated from THP-1 monocytes employing Phorbol 12-Myristate 13-Acetate (PMA) and lipopolysaccharide (LPS). Then, macrophage activity was determined based on Mean Fluorescence Intensity (MFI), and their metabolic capacity was assessed according to extracellular acidification rate (ECAR) and Oxygen Consumption Rate (OCR). Quantitative Real-Time PCR (qRT-PCR) was performed to assess the expression of polarization-related genes.

The results showed that LPS at a concentration higher than 10 ng/mL significantly affected the viability of macrophages differentiated from THP-1 monocytes but promoted the MFI of CD86. At the same time, LPS treatment notably enhanced the M1 polarization of macrophages, as evidenced by the upregulated expression of markers related to the M1 phenotype. Moreover, the mitochondrial oxidative metabolism of M1 macrophages shifted toward aerobic glycolysis under LPS treatment. When T-cells and HCC cells were co-cultured with M1 macrophages, the reactivity of T cells was enhanced, and the level of Bax (an apoptosis-enhancer) was increased. At the same time, the expression of Bcl-2 (an apoptosis-suppressor) was suppressed.

LPS-induced M1 macrophages exert antitumor effects through metabolic reprogramming and immune modulation, though further mechanistic studies are needed.

M1 macrophages inhibit HCC progression by activating T cells and inducing tumor cell apoptosis, offering novel insights for HCC immunotherapy.

The link between telomere length and Colorectal Cancer (CRC) risk and survival has been established. This study aims to investigate Telomere Maintenance-related Genes (TMGs) for predicting immunotherapy response and prognosis in CRC patients.

In this study, gene expression data and clinical information of CRC patients were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and TMG-related scores were calculated for the samples. Subsequently, Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify gene modules that were highly correlated with the TMG score and intersected with differentially expressed genes to screen for potential functionally relevant candidate genes. The key genes significantly associated with prognosis were further analyzed using Cox regression analysis, from which the key genes were identified, and a risk score model was constructed. Finally, the survival prediction ability of the model was evaluated across multiple cohorts, and differences in immune cell infiltration characteristics and drug sensitivity were analyzed within different risk groups.

A higher TMG score was noticed in CRC, and the TMG score was negatively correlated with the StromalScore, ImmuneScore, and ESTIMATEScore. Gene modules significantly associated with the TMG score were identified using WGCNA. Two key genes, CDC25C and USP39, which were closely associated with prognosis, were screened through differential expression analysis, and a risk score model was constructed. The model showed good survival prediction in both TCGA and GSE17537 independent cohorts. The scores of activated CD4 T cells, Type 17 T helper cells, Type 2 T helper cells, and neutrophils in high-risk patients were lower, while that of macrophages was higher in high-risk patients. Additionally, a negative correlation was observed between the risk score and the IC50 values of most drugs, as well as the enriched pathways of patients at high risk, which included epithelial-mesenchymal transition, angiogenesis, and myogenesis.

This study unveiled a TMG-related signature that predicts prognosis and immunotherapy in CRC. Based on the 2 prognostically relevant genes CDC25C and USP39, a reliable risk score model was established for the prognostic prediction, and the correlation between the drug sensitivity and the risk score was also explored.

This study reveals the significant value of TMGs in CRC prognostic assessment and immunotherapy response prediction, providing a new molecular basis for the development of individualized treatment strategies.

Skin cutaneous melanoma (SKCM) is a life-threatening malignancy, and pyroptosis-mediated inflammatory response is associated with SKCM progression. We aimed to uncover the underlying pathogenesis of SKCM based on pyroptosis features.

The single-cell and bulk RNA-seq data and clinical information of SKCM patients were downloaded from the TCGA and GEO databases, and the REACTOME_PYROPTOSIS.v2024.1.Hs.gmt from the MSigDB database was used for Gene Set Enrichment Analysis (GSEA). Differentially expressed gene (DEG) analysis was performed utilizing the “limma” R package, and the “GSVA” R package was used for the analysis of pyroptosis pathway activation. In addition, scRNA-seq analysis and cell communication analysis were carried out by employing the “Seurat” R package and “CellChat” R package, respectively. Gene expression was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR), while cell counting kit-8 (CCK-8), wound healing, and Transwell assays were carried out to assess cell proliferation, migration, and invasion, respectively.

DEGs analysis detected no significant pyroptosis-related DEGs. Analysis of the expression of two representative pyroptosis genes (GZMA and GSDMB) revealed that GZMA was significantly upregulated in the SKCM tissues, but the expression of GSDMB was downregulated. The pyroptosis pathway was not activated in the tumor group. In addition, we observed that high expression of GZMA and GSDMB was closely associated with a favorable outcome in SKCM. The two genes were downregulated in SKCM cells, while the overexpression of GZMA significantly impaired the proliferation, migration, and invasion ability of SKCM cells. Nine main cell subpopulations were identified, and GZMA was specifically overexpressed in CD8+ T cells. Gene function analysis revealed that specific genes of CD8+ T cells were enriched in cell death-related and inflammation activation pathways. Cell communication demonstrated that CD8+ T cells interacted with melanocytes through the CD99-CD99 and HLA-C-KIR2DL3 ligand-receptor pairs.

Based on the pyroptosis features in SKCM, this study found that blocking GZMA protein in CD8+ T cells within melanocytes may be the potential underlying pathogenesis for tumor immune escape in cancer.