Current Medicinal Chemistry - Volume 32, Issue 35, 2025

The PANoptosis pathway is a recently identified mechanism of cellular death that involves the interaction and synchronization among cellular pyroptosis, apoptosis, and necrosis. More and more evidence suggests that PANoptosis is involved in the development and treatment of cancer. However, a comprehensive understanding of the influence of PANoptosis genes on prognostic value, tumor microenvironment characteristics, and therapeutic outcomes in patients with ovarian cancer (OC) remains incomplete.

The present work was designed to devise a PANoptosis signature for OC prognosis and explore its potential molecular function.

For this study, we obtained RNA sequencing and clinical data for ovarian cancer from the Cancer Genome Atlas (TCGA) and the GSE32062 cohort. Somatic variants of PANoptosis-related genes (PRGs) in OC were analyzed using GSCA. TCGA-OC and GSE32062 were used to construct training and validation cohorts for the model. Differential expression and correlation analyses were performed following the screening of genes with prognostic ability using univariate Cox analysis. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed to construct PRG signature based on genes that were differentially expressed and correlated with prognosis. CIBERSORT and ESTIMATE were used to analyze the relationship between the PRGs signature and immune infiltration. TIDE was used to analyze the relationship between the PRG signature and immune checkpoint genes. OncoPredict was used to analyze the relationship between the PRG signature and the drug sensitivity. Quantitative real-time PCR (qRT-PCR) was used to validate the expression of PRGs in OC.

The PRG signature was constructed using three prognostic genes (AIM2, APAF1, and ZBP1) in both TCGA-OC. The results showed that the PRGs signature had an AUC of 0.521, 0.546, and 0.598 in TCGA-OC and 0.620, 0.586, and 0.579 in GSE32062 to predict to predict OS at 1-, 3-, and 5-year intervals. Furthermore, a higher PRG signature risk score was significantly associated with shorter OS (HR = 1.693, 95% CI: 1.303 - 2.202, p = 8.34 × 10^-5 in TCGA-OC and HR = 1.63, 95% CI: 1.13 - 2.35, p = 0.009 in GSE32062). The risk score was identified as the independent prognostic factor for OC. Patients categorized according to their risk score exhibited notable variations in immune status, response to immunotherapy, and sensitivity to drugs. AIM2, APAF1, and ZBP1 were significantly aberrantly expressed in OC cell lines.

The PRG signature has the potential to serve as a prognostic predictor for OC and to provide new insights into OC treatment.

As the most common subtype of colorectal cancer, colorectal adenocarcinoma (COAD) still needs better prognostic stratification methods and new intervention targets. The mitochondrial stress response, linked to mitochondrial homeostasis and cancer metabolism, warrants further investigation.

We identified mitochondrial oxidative stress-related genes (MOS) associated with COAD prognosis through the TCGA and GEO databases. Molecular subtype characteristics were identified based on MOS gene signatures, and an MOS scoring system was established to comprehensively evaluate its clinical value. Additionally, the effect of one of the screened genes, NDRG1, was investigated through a series of in vitro experiments, including Western blot, qRT-PCR, CCK8 assay, clone formation, and Transwell assay, to explore its impact on COAD proliferation and migration ability.

Our analysis revealed that MOS gene signatures effectively distinguished molecular subtypes of COAD, and the MOS scoring system was found to be independent in predicting prognosis. Evaluation of microenvironment infiltration characteristics, mutation characteristics, immunotherapy response, and drug sensitivity analysis further suggested the potential clinical utility of this study. In vitro experimental results showed that NDRG1 significantly affected the proliferation and migration of COAD cells, partially verifying the reliability of our bioinformatics analysis.

This study provides a novel perspective on the role of mitochondrial oxidative stress in COAD, proposing innovative prognostic evaluation methods and potential therapeutic targets, thus offering new directions for the clinical treatment of COAD.

Triple-Negative Breast Cancer (TNBC) is the most common type of breast cancer (BC). In order to develop effective treatments for TNBC, it is vital to identify potential therapeutic targets. Angiogenesis stimulates tumor growth and metastasis in TNBC, and miR-155 plays a crucial role in this process. The exosome is a nano-sized vesicle that carries many cargoes, including miRNAs. The present study investigated the effect of exosomal delivery of miR-155 antagomir on tumor migration, invasion, and angiogenesis in TNBC.

From MDA-MB-231 cells, exosomes were extracted, characterized, and loaded with miR-155 antagomir using electroporation. The expression of miR-155 and its target genes, including PTEN and DUSP14, was analyzed using RT-qPCR. The wound-healing and transwell assays were used to measure cell migration and invasion. Furthermore, angiogenesis was evaluated by tube formation and chorioallantoic membrane (CAM) assays.

The results indicated that exosomal delivery of miR-155 antagomir to HUVEC cells significantly suppressed miR-155 expression while upregulating PTEN and DUSP14. The tube formation properties of HUVEC cells were also significantly reduced following treatment with exosomes containing miR-155 antagomirs, and these results were confirmed using CAM assay. The migration and invasion of MDA-MB-231 cells were significantly reduced after treatment with miR-155 antagomir-loaded exosomes.

It was found that miR-155 antagomir delivery using exosomes can inhibit migration, invasion, and angiogenesis via PTEN and DUSP14 in TNBC.

The role of LNX1 antisense RNA 2 (LNX1-AS2) in lung adenocarcinoma (LUAD) remains unclear.

This study aimed to investigate the association between LNX1-AS2 and LUAD by employing bioinformatics analysis and experimental validation.

Statistical analysis and database interrogation were utilized to assess correlations among LNX1-AS2 expression, clinical characteristics of LUAD patients, prognostic factors, regulatory networks, and immune infiltration. LNX1-AS2 expression in LUAD cell lines was quantified using quantitative real-time polymerase chain reaction (qRT-PCR).

The study found significantly elevated levels of LNX1-AS2 expression in patients with LUAD. Furthermore, elevated LNX1-AS2 expression in LUAD patients did not significantly correlate with gender (p = 0.041) or race (p = 0.049). Importantly, high LNX1-AS2 expression levels were associated with poorer overall survival (OS, p = 0.042) and disease-specific survival (DSS, p = 0.040) in LUAD patients. Additionally, high LNX1-AS2 expression (p = 0.015) was independently correlated with OS in LUAD patients. The phenotype characterized by high LNX1-AS2 expression was also found to be enriched for asthma, allograft rejection, drug metabolism cytochrome P450, metabolism of xenobiotics by cytochrome P450, olfactory transduction, renin-angiotensin system, retinol metabolism, pentose and glucuronate interconversions, and porphyrin and chlorophyll metabolism. A significant correlation was identified between the expression levels of LNX1-AS2 and immune infiltration in the context of LUAD. Elevated expression of LNX1-AS2 was notably detected in LUAD cell lines as opposed to Beas-2B.

A noteworthy relationship was established among increased LNX1-AS2 expression in LUAD patients, unfavorable prognosis, and heightened immune infiltration. These findings suggest that the LNX1-AS2 gene could serve as a valuable prognostic indicator for LUAD and a potential predictor of response to immunotherapy.

The potential role of the iroquois homeobox (IRX) genes in tumorigenesis is a subject of interest, yet their specific involvement in lung adenocarcinoma (LUAD) has not been extensively examined.

This research endeavored to explore the impact of the IRX genes on the onset and progression of LUAD.

Utilizing data from The Cancer Genome Atlas (TCGA), samples of LUAD were selected for analysis. The influence of the IRX genes was scrutinized through various tools, including Kaplan-Meier Plotter, cBioPortal, and the R programming language (version 3.6.3), with gene expression levels being confirmed in cellular models via quantitative real-time polymerase chain reaction (qRT-PCR).

It was observed that the levels of IRX1/2/3/6 were notably diminished in LUAD tissues when juxtaposed with healthy lung tissue. Conversely, the expression of IRX4 was found to be elevated in LUAD. Correlations were identified between IRX gene expression and several clinical parameters such as T stage, smoking history quantified in pack-years, lymph node involvement, patient gender, initial treatment responses, and smoking status. The diminished expression of IRX2/5 emerged as a significant indicator of an unfavorable prognosis in LUAD. The study also highlighted the potential of various IRX genes as diagnostic indicators for LUAD. These genes were implicated in the facilitation of LUAD's growth and spread through a range of biological pathways, encompassing the Ras signaling and more. Additionally, a pronounced link was discovered between the infiltration of immune cells and the expression patterns of the IRX genes. IRX genes were abnormally expressed in LUAD cell lines.

IRX gene family could serve not only as indicators of LUAD prognosis but also as therapeutic targets for LUAD.

The high prevalence of non-alcoholic Fatty Liver Disease (NAFLD), a chronic progressive disease characterized by hepatic steatosis, poses a serious burden to human health. Depression and NAFLD share some common pathogenic mechanisms, and patients with depression are at an increased risk of NAFLD. The drug mirtazapine is commonly used in the treatment of depression, but it can also cause liver damage. However, whether mirtazapine induces or aggravates NAFLD remains uncertain. Thus, we evaluated the risk factors for NAFLD in patients with depression and the effects of mirtazapine on NAFLD in vitro.

Inpatients diagnosed with depression at the Second Xiangya Hospital of Central South University between 2019 and 2022 were included in this study, and NAFLD was determined using an abdominal ultrasound examination. The risk factors for the development of NAFLD in patients with depression were analyzed using logistic regression analysis. AML-12 and MIHA cell lines were used to observe the effects of mirtazapine on NAFLD using oil red O staining. RT-qPCR and Western blotting were used to explore the molecular mechanism behind NAFLD development induced by mirtazapine.

Logistic regression analysis showed that older age, use of mirtazapine or fluoxetine, longer duration of antidepressant use, and combined hyperlipidemia or T2DM were risk factors for NAFLD in patients with depression. In vitro experiments revealed a subsequent increase in the content of intracellular lipid droplets as mirtazapine concentration increased. Mechanistic studies showed that mirtazapine increased the expressions of TLR4, MyD88, IFN-γ, IL-1β, IL-6, and TNF-α mRNA in hepatocytes and the expressions of TLR4, MyD88, and p-NF-κB-p65 proteins in a dose-dependent manner.

Age, antidepressant type, duration of antidepressant use, and comorbidities could be risk factors for NAFLD in patients with depression. Furthermore, mirtazapine can cause steatosis in both AML-12 and MIHA cell lines and may promote the development of NAFLD through the TLR4/MyD88/NF-κB signaling pathway. This study lays a solid foundation for further research on depression and NAFLD and can contribute to the prevention and treatment of these two diseases.

Chagas disease (CD), a life-threatening disease caused by Trypanosoma cruzi, remains a significant global public health concern. The limited efficacy of the available drugs (nifurtimox and benznidazole), their severe adverse events, and the unsatisfactory outcomes of clinical trials drive the search for new, effective, and safe drugs.

This study describes the synthesis, structural characterization, and in vitro antiparasitic activity of novel pyrazole-benzimidazole derivatives against mammalian developmental stages of T. cruzi.

Phenotypic screening was used to assess the effect of pyrazole-benzimidazole derivatives against T. cruzi. Three-dimensional cardiac spheroids were employed to evaluate the toxic effect and drug efficacy. Molecular docking and cysteine protease activity were also performed.

Pyrazole-benzimidazole derivatives showed activity against both trypomastigotes and intracellular amastigotes. Compounds 1i (IC50 = 6.6 µM) and 1j (IC50 = 9.4 µM) demonstrated the most potent activity with a high selectivity index (SI > 45) against intracellular amastigotes. Both compounds exhibited high efficacy on 3D cardiac spheroids, effectively reducing the parasite load by over 80%. Molecular docking analysis revealed that both compounds target the catalytic domain of cruzain through pi-stacking and hydrogen bonding interactions and inhibit T. cruzi cysteine protease. These derivatives also showed an additive effect in combination with the reference drug (Bz).

Our findings emphasize the significance of pyrazole-benzimidazole hybrids in the search for new anti-T. cruzi agents.

The use of bioactive molecules isolated from rattlesnake venom and other poisons has been ongoing for years. Among these bioactive compounds present in snake venom, crotoxin (CTX) stands out as a β-heterodimeric neurotoxin isolated from the venom of Crotalus durissus terrificus. Research on this toxin for its applicability to tumor inhibition has advanced to clinical trials in recent years. Consequently, concerns regarding the use of a toxin as a treatment and the search for dose control that does not trigger extreme toxicity have emerged. Thus, it is necessary to investigate alternatives for controlled delivery and targeted toxin administration.

This study aimed to evaluate the in vitro toxic action of CTX and its phospholipase A2 CB (PLA2CB) component, both free and encapsulated in polymeric nanoparticles. The inhibitory concentration value of 50% tumor growth (IC50) for CTX and PLA2CB was determined in an initial screening against six tumor cell lines. After identifying the lowest inhibitory concentration value of 0.8 μM observed in human melanoma (SK-MEL-103), this cell line was chosen.

The cell death mechanism triggered by CTX and PLA2CB exhibited characteristics associated with the necrotic process. However, polymeric nanoparticles containing PLA2CB (NP-PLA2CB) demonstrated apoptosis-like cell death processes in flow cytometry. PLGA polymeric nanoparticles containing PLA2CB were synthesized using microfluidics, resulting in NP-PLA2CB with a diameter of 91 ± 2.9 nm and a zeta potential of -21.8 ± 3.2 mV. The encapsulation efficiency of PLA2CB was approximately 70% (protein content).

It was concluded that using the phospholipase component of the toxin in a polymeric-controlled delivery and targeted system may be an alternative solution to the issues in advancing this bioactive molecule in clinical-oncological studies. However, further studies are still being conducted for targeted treatment involving this nanotechnological approach.