TOP2A (DNA topoisomerase 2-alpha)

These findings highlight the therapeutic potential of WGX-50 as a multitarget anticancer agent capable of modulating multiple signaling cascades. This Insilico study provides valuable insights into the development of targeted therapies for BC, NSCLC, and presents WGX-50 as a promising anticancer candidate.

Although survival analyses did not demonstrate statistically significant independent prognostic associations, the findings support the biological relevance of CDK1 and TOP2A in EOC progression. Collectively, this study provides an integrated computational perspective on CDK1/TOP2A-associated oncogenic signaling and prioritizes Naringin as a preliminary candidate for future experimental investigation in epithelial ovarian cancer.

Consistent with this, barettin inhibits TOPO2α-mediated DNA decatenation in vitro, demonstrating direct interference with enzyme activity. These findings support barettin as a selective inhibitor of a cancer-relevant proliferative pathway, uncovering a potential vulnerability in a subset of PDAC.

Targeting this vulnerability, THOC2 knockdown induced synthetic lethality with PARPi, reducing Olaparib IC50 by up to 61% and suppressing tumor growth by 76% (P<0.001). Our study illuminates mRNA transport as a druggable DDR modulator and establishes THOC2 as both a prognostic biomarker and a therapeutic target to overcome PARPi resistance in HCC. This work pioneers a strategy to expand synthetic lethality beyond genetic defects by targeting post-transcriptional regulation.

Our study identifies a four-gene cell cycle signature associated with poor LUAD prognosis and demonstrates that astragalin induces apoptosis in LUAD cells. These genes are involved in a PANoptosis-related network, suggesting a potential mechanistic link requiring further validation.

This comprehensive single-cell transcriptomic analysis successfully characterized the cellular heterogeneity of glioma, identifying distinct cell populations and molecular signatures. PLP1, FTH1, and GM42418 were validated as potential molecular biomarkers, providing novel insights into glioma pathogenesis and potential therapeutic targets.

Functional experiments showed that TOP2A knockdown inhibited proliferation, migration, and invasion of NB cells. We established an eight-gene PANoptosis-related prognostic index for neuroblastoma and highlighted four hub genes (KIF18A, EXO1, TOP2A, and TACC3) closely associated with NB risk and prognosis.

PLD demonstrated modest efficacy in metastatic BC lacking HER2 overexpression, with comparable outcomes in HER2-low and HER2-negative subgroups. These findings suggest that HER2-low status does not predict anthracycline benefit and support the view that HER2-low is unlikely to represent a distinct therapeutic subtype. Further research is needed to refine treatment selection in this heterogeneous population.

This integrated computational study prioritized a five-gene framework potentially linking OTA-related predicted targets with CRC-associated metabolic and immune-related molecular alterations. These findings are supported by immune contexture inference, external protein-level reference data, computational structural analyses, and single-cell-based in silico perturbation results, providing a hypothesis-generating framework for subsequent experimental investigations into the potential toxicological relevance of OTA in CRC.

The resulting splice site gene-edited clone, designated MX2/SS-Edit, expressed reduced TOP2α/160 mRNA/protein, increased TOP2α/170 mRNA/protein, and exhibited partial restoration of sensitivity to mitoxantrone, etoposide, and amsacrine. SIGNIFICANCE STATEMENT: Results presented here validated drug resistance in the HL-60/MX2 leukemia cell line driven by intronic polyadenylation (IPA) within intron 33 of the DNA topoisomerase IIα (TOP2α) gene, which produced a truncated and predominantly cytoplasmic TOP2α protein isoform (TOP2α/160). Using CRISPR/Cas9/homology-directed repair gene editing, the weak exon 33/intron 33 5' splice site was enhanced to suppress IPA, which restored expression of full-length protein (TOP2α/170) and led to a gain-of-function in drug sensitivity, offering a potential strategy to overcome drug resistance.

Redocking of co-crystallized ligands yielded RMSD values below 2.0 Å, supporting protocol reliability. Overall, these findings suggest preliminary dark-condition in vitro activity of SiPc (Tan et al., 2020 (4)) and SubPc (Weller et al., 2021 (5)) against U-87 MG cells, while the docking results offer hypothesis-generating molecular insight into possible target interactions that may support future mechanistic and optimization studies.

This integrative study provides a comprehensive single‑cell and spatial atlas of baicalein‑responsive genes in NSCLC, identifies a robust diagnostic signature, and offers mechanistic insights for developing baicalein as a potential therapeutic agent.