Tumor angiogenesis is a hallmark of cancer, influencing oxygen delivery, immune cell trafficking, and therapeutic response. Although anti-angiogenic therapies have achieved clinical relevance, their efficacy remains limited by tumor heterogeneity, adaptive resistance, and insufficient functional assessment of tumor vasculature. In this review, we evaluate preclinical models of tumor angiogenesis with a focus on their ability to generate quantitative and physiologically relevant readouts. We discuss established assays such as tube formation, fibrin bead assay, aortic ring, and chorioallantoic membrane (CAM) models, alongside emerging systems including vascularized organoids and organ-on-a-chip platforms, as well as zebrafish and murine tumor models. Particular emphasis is placed on advanced imaging modalities enabling longitudinal assessment of perfusion, permeability, and vascular remodeling, as well as on the growing role of artificial intelligence (AI) in automated and quantitative data interpretation. We further highlight the integration of single-cell and multi-omics approaches for resolving endothelial heterogeneity and tumor-stroma interactions. By linking biologically relevant models with functional imaging and computational analysis, this review outlines strategies to improve the predictive power and translational relevance of angiogenesis research.

Brain tumors, including gliomas and neuroblastoma (NB), remain among the most aggressive and therapeutically challenging malignancies of the nervous system. Despite multimodal treatment, prognosis for high-grade gliomas and high-risk NB remains poor, largely due to pharmacological barriers and intrinsic therapy resistance. Isoflavones are plant-derived phytoestrogens that have attracted increasing attention because of their pleiotropic anticancer, anti-inflammatory, and neuroprotective properties. In this review, we focus on the molecular and cellular mechanisms that determine the biological activity of isoflavones in brain tumors, including estrogen receptor-dependent signaling, modulation of oncogenic pathways, and limitations related to blood-brain barrier permeability. We discuss how modulation of phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), and nuclear factor kappa B (NF-κB) pathways contributes to antiproliferative and pro-apoptotic effects, and how limited brain bioavailability represents a major barrier to effective application. We identify key limitations of the current literature, including inconsistent epidemiological findings, poor standardization of experimental models, and limited pharmacokinetic characterization. Available data suggest that isoflavones represent promising adjuncts in brain tumor therapy, but their clinical relevance will depend on improving brain delivery and defining receptor-selective mechanisms of action.

Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and the failure of cellular antioxidant defenses. Its close integration with iron metabolism, lipid remodeling, and redox homeostasis has identified ferroptosis as a potentially exploitable vulnerability in cancer. This review critically examines the molecular and pharmacological determinants of ferroptotic sensitivity, including iron handling, acyl-CoA synthetase long-chain family member 4 (ACSL4)/lysophosphatidylcholine acyltransferase 3 (LPCAT3)-dependent lipid remodeling, and the glutathione peroxidase 4 (GPX4)-glutathione, ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10, mitochondrial dihydroorotate dehydrogenase (DHODH), and GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin defense systems. We discuss experimental ferroptosis inducers and clinically used drugs with reported ferroptosis-modulating activity, emphasizing differences in their mechanisms, strength of evidence, and translational relevance. Particular attention is given to the bidirectional interactions between ferroptosis and the tumor immune microenvironment. Although cytotoxic lymphocytes and interferon-gamma (IFN-γ) signaling may sensitize malignant cells to ferroptosis, excessive lipid peroxidation in cluster of differentiation 8-positive (CD8⁺) T cells, natural killer cells, dendritic cells, and other immune populations may impair antitumor immunity. These context- and cell-type-dependent effects support combination strategies involving immunotherapy, radiotherapy, and conventional or targeted anticancer treatments, but also define potential toxicities. We further discuss candidate biomarkers related to iron metabolism, lipid composition, antioxidant capacity, and immune context, as well as the need for patient stratification and targeted drug delivery. Successful clinical implementation will require selective induction of ferroptosis in malignant cells while preserving normal tissues and antitumor immune function. Ferroptosis should therefore be regarded as a conditional therapeutic vulnerability rather than a universally beneficial anticancer mechanism.

The endocannabinoid system (ECS) is a highly plastic signaling network whose components are dynamically regulated in a context-dependent manner. Among its components, the cannabinoid type 1 receptor (CB1R), encoded by the CNR1 gene, is involved in multiple processes, including neuromodulation, neurodevelopment, metabolic regulation, nociception, appetite regulation, redox homeostasis, and inflammatory signaling. Alterations in CB1R expression occur selectively and progressively and have been linked to numerous metabolic disorders, cancer, and neurodegenerative diseases. Recent studies have begun to unveil the transcriptional and epigenetic mechanisms regulating CB1R expression, involving inflammatory transcription factors, nuclear receptors, metabolic regulators, redox-sensitive pathways, hormone-responsive factors, as well as chromatin remodeling marks and promoter methylation. These modulatory programs collectively shape CB1R abundance and availability and may critically influence the efficacy and safety of cannabinoid-based therapies. In this review, we discuss current knowledge of the transcriptional and epigenetic regulation of the CNR1 gene in response to various pathologies and drugs, highlighting context-dependent modulatory mechanisms. Additionally, we performed an in silico analysis to identify potential transcription factor binding sites (TFBS) in the CNR1 promoter and to elucidate candidate regulatory networks underlying its differential expression in health and disease.

Cancer therapy-related cognitive impairment (CRCI) is a frequent complication of cancer treatment. It involves multiple biological mechanisms: neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired neurogenesis, and altered brain connectivity. Although these mechanisms have been extensively studied, evidence across cytotoxic chemotherapy, endocrine therapy, and targeted therapies is often presented separately. This review is the first of a two-part series addressing the mechanisms underlying CRCI and current and emerging therapeutic strategies for its prevention and management. It integrates available clinical and mechanistic research results across treatment classes, highlighting shared biological pathways, biomarkers, neuroimaging findings, and objective versus subjective cognitive outcomes to provide a comprehensive overview of CRCI.

Although numerous pharmacological and nonpharmacological strategies have been proposed for the prevention or treatment of cancer therapy-related cognitive impairment (CRCI), only a few have achieved robust clinical translation. This review, the second part of a two-part series, first critically summarizes current candidate pharmacological and nonpharmacological interventions for CRCI, discussing their biological rationale, mechanisms of action, and the available preclinical and clinical evidence. It then reports why many of these promising approaches fail to translate into effective clinical therapies. We critically analyse the methodological gaps between preclinical models and cancer survivorship, including the use of non-tumour-bearing animals, inadequate modelling of age, sex, and hormonal status, mismatched behavioural and clinical endpoints, poor biomarker alignment, and insufficient assessment of potential interactions between neuroprotective agents and anticancer efficacy. Finally, we propose a translational roadmap for developing mechanism-informed, clinically predictive, and oncologically safe interventions for CRCI and explain why the preclinical efficacy of many candidate therapies has not yet translated into robust clinical benefit.

The human gut microbiota (GMB) has a significant impact on physiological function, including gastrointestinal health, immune regulation, and redox homeostasis. It consists of diverse microorganisms that support digestion, nutrient absorption, and intestinal barrier function. Emerging evidence suggests that gut microbiota-derived metabolites may influence the gut-brain axis and regulate epigenetic mechanisms through modulation of histone deacetylases (HDAC). HDAC are key enzymes involved in gene expression, neuronal survival, neuroinflammation, and the pathogenesis of Alzheimer's disease (AD). Gut microbiota-derived metabolites have been reported to modulate HDAC activity and may contribute to neuroprotective and anti-inflammatory effects. Through these mechanisms, the GMB may influence cognitive function and the progression of AD. However, the precise molecular mechanisms involved in these interactions are not yet fully understood and continue to be extensively investigated. Therefore, this review focuses on the correlation between HDAC and the restoration of a healthy GMB as a therapeutic approach for the treatment and prevention of AD. It emphasizes the role of gut-derived metabolites, peptides, and dietary bioactive compounds in regulating HDAC-mediated epigenetic pathways. These interactions may influence gene expression, neurotransmitter biosynthesis, neuroinflammation, and neuroprotective signalling associated with cognitive function. Furthermore, the review delineates the bidirectional interplay among neurotransmitter signalling, GMB composition, and HDAC-mediated epigenetic regulation, along with their potential roles in the pathophysiology of neurodegenerative disorders.