Solid tumors are not only genetic and cellular diseases but also spatially organized physical ecosystems in which architecture strongly influences therapy resistance and clinical outcome. Emerging spatial proteomics suggests that tumor topology, how cancer cells, immune cells, vessels, and extracellular matrix are arranged, can determine whether immune infiltration, drug penetration, and metastatic spread are promoted or blocked. In this perspective, we propose Geometric Therapeutics, a conceptual framework that repurposes existing pharmacological agents to reshape tumor architecture by restoring strategic empty space. Although significant translational and safety challenges remain, the central message is clear: tumor emptiness is not absence, but opportunity. Reframing cancer treatment through geometry may provide a new route to augment existing therapies without requiring entirely new drugs.
Poly(ADP-ribose) polymerase 1 (PARP1) is a key guardian of genome integrity and a major therapeutic target in cancer. Although its catalytic activation has been extensively studied, how PARP1 is restrained under physiological conditions yet rapidly mobilized following DNA damage has remained unclear. In this issue, Shu et al. (2026) identify poly(rC)-binding protein 1 (PCBP1) as an endogenous gatekeeper that restricts PARP1 access to damaged DNA. DNA double-strand breaks trigger SIRT7-dependent deacetylation of PCBP1, releasing this brake and enabling PARP1 to initiate DNA damage signaling. Beyond identifying a new regulator, this work uncovers an upstream licensing step in PARP1 activation and points to an alternative strategy for modulating PARP1 that complements conventional catalytic inhibition.
Oxidative stress is a major pathogenic driver across disorders in which persistent redox imbalance promotes cellular injury, inflammation, mitochondrial dysfunction, and maladaptive survival responses. Circular RNAs (circRNAs) have emerged as post-transcriptional regulators of these processes by modulating circRNA–miRNA–mRNA networks, antioxidant gene programs, redox-sensitive signalling pathways, and ROS-generating enzymes. This review examines how circRNAs influence Nrf2, NF-κB, MAPK, PI3K/AKT, mitochondrial, and cell-death pathways in cancer, neurodegenerative, cardiovascular, and metabolic diseases. Rather than cataloguing disease-associated circRNAs, we apply a redox-centred, evidence-tiered, and context-dependent framework that distinguishes mechanistic support from associative findings and highlights why the same circRNA may exert protective or pathogenic effects across tissues and disease states. We further evaluate the diagnostic potential of circulating and tissue-specific circRNAs and the therapeutic relevance of synthetic circRNAs, antisense strategies, and CRISPR/Cas-based modulation. These approaches may enable pathway-directed biomarker development and targeted redox intervention, but their clinical value remains constrained by limited human validation, inconsistent circRNA and ROS assays, off-target effects, delivery barriers, immunogenicity, and uncertainty regarding host-gene disruption. Standardized methodologies, longitudinal cohorts, and integrated multi-omics studies are therefore required to establish causality, reproducibility, and translational readiness.
Tumorigenesis occurs due to changes in both coding and non-coding regions of the genome. While researchers have studied protein-coding mutations in detail, the role of non-coding variants is less understood. In this study, we employed a computational framework to investigate changes in the dark DNA, including intronic single nucleotide variants (SNVs) and copy number variations (CNVs), in genes on human chromosome 1 (T2T-CHM13v2.0 assembly). We conducted expression profiling, followed by enrichment analysis, mutational mapping, CNV annotation, and drug-gene interaction studies. To fine-tune the Notch pathway, we docked NOTCH2 harboring an intronic single nucleotide variant (SNV) with six curcuma molecules and recorded the binding affinity. Protein-protein interaction (PPI) networks, along with enrichment analysis, identified 9 genes involved in various oncogenic pathways. The hubs identified were pivotal for cancer progression. CNVs that affect regulatory elements, especially promoters, enhancers, and epigenetically modified accessible regions, were strongly linked to changes in the expression of NOTCH2 and NRAS. Drug-gene interaction analysis highlighted Tazarotene (TP73) and Odevixibat (NOTCH2) as high-priority candidates for therapeutic repurposing. Docking studies revealed promising binding conformations and strong interactions between the modeled NOTCH2 protein and selected ligands, suggesting their potential as modulators of oncogenic pathways. Collectively, these findings underscore that non-coding structural alterations play a critical role in regulating cancer pathways and represent promising biomarkers and therapeutic targets in solid tumors.
Colorectal cancer (CRC) continues to represent one of the leading causes of cancer-related morbidity and mortality, globally. Natural phytochemicals from Commiphora wightii (C. wightii) has recently garnered attention as possible anticancer agents due to their multi-targeting mechanisms. The aim of this study was to investigate the molecular mechanisms of inhibition for these phytochemicals against CRC, via an integrated in silico approach. Potential targets of C. wightii phytochemicals and CRC-associated genes were retrieved from publicly available databases. Overlapping targets were identified using Venn analysis, which were subjected to protein-protein interaction (PPI) network construction and hub gene selection using Cytoscape and CytoHubba. Functional enrichment was performed through Gene Ontology (GO) and KEGG pathway analyses. The expression and prognostic significance of hub genes were evaluated using GEPIA2 and Kaplan–Meier survival analysis. Immune infiltration correlations were assessed using TIMER 3.0, and molecular docking was performed using CB-Dock2 to explore binding affinities of phytochemicals with hub proteins. A total of 85 overlapping targets were identified between C. wightii phytochemicals and CRC-associated genes. Network analysis revealed ten hub genes, among which MET, CDK1, MMP9, PLAU, and CCND1 were significantly upregulated in CRC tissues. Immune infiltration analysis demonstrated significant association of MMP9 and PLAU with macrophage infiltration in both COAD and READ, suggesting their potential role in modulating the tumor immune microenvironment. Molecular docking revealed strong binding affinities of E-Guggulsterol toward MMP9 (-10.6 kcal/mol) and MET (-9.4 kcal/mol), while Quercetin showed favorable interactions with PLAU (-8.5 kcal/mol), MMP9 (-8.7 kcal/mol), and MET (-8.3 kcal/mol). These findings highlight E-Guggulsterol-MMP9, E-Guggulsterol-MET, Quercetin-PLAU, and Quercetin-MET as promising compound-target pairs for further investigations. This study identified key CRC-associated targets potentially modulated by C. wightii phytochemicals. Integrated network pharmacology, immune infiltration, and molecular docking analyses highlighted MMP9, PLAU, and MET as biologically relevant targets. E-Guggulsterol and Quercetin demonstrated favorable interactions with these proteins, particularly E-Guggulsterol-MMP9, E-Guggulsterol-MET, Quercetin-PLAU, and Quercetin-MET, suggesting their potential as lead compounds for CRC therapy. Since this work relies on in silico analysis, we call for further in vitro and in vivo studies to support our findings and check if these effects could have therapeutic implications. Network pharmacology identified 10 CRC-associated hub gene targets of Commiphora wightii phytochemicals. MMP9 and PLAU were strongly associated with macrophage infiltration, suggesting immunomodulatory roles. E-Guggulsterol showed the strongest binding toward MMP9 (-10.6 kcal/mol) and MET (-9.4 kcal/mol). Quercetin exhibited favorable interactions with PLAU, MMP9, and MET. E-Guggulsterol-MMP9, E-Guggulsterol-MET, Quercetin-PLAU, and Quercetin-MET were suggested for future validation.
