Colorectal cancer (CRC) remains a leading cause of cancer morbidity worldwide, highlighting the need for improved therapies. Metformin, a widely used antihyperglycemic agent, has gained attention for its potential antitumor properties. In this study, we evaluated the effects of the tumor suppressor genes TP53 and CDKN1A on metformin responsiveness in a KRAS-mutant CRC in vitro model using HCT116 cells harboring a G13D mutation in KRAS. Using parental (p53^+/+, p21^+/+) and isogenic knockout cell lines, we assessed cell-cycle distribution and transcriptomic responses following metformin treatment. In parental wild-type cells, metformin exposure was associated with a dose- and time-dependent reduction in cell viability and an increased proportion of cells in the G0/G1 phase, with significance levels across treatment conditions ranging from p = 0.03 to p < 0.0001. Loss of p53 or p21 was associated with attenuated cellular responses to metformin, with p21-deficient cells responding primarily at higher doses and prolonged exposure (72 h). Transcriptomic profiling revealed extensive differential gene expression in parental cells (1399 DEGs), compared with more limited responses in p53^−/− (270 DEGs) and p21^−/− cells (32 DEGs). Differentially expressed genes associated with MAPK signaling (DUSP5) and inflammatory regulation (TNFAIP3) were observed across genotypes, whereas pathway enrichment of DNA replication and chromatin organization was specific to p53-deficient cells. These findings provide a transcriptomic and phenotypic characterization of genotype-dependent cellular responses to metformin and establish a basis for future mechanistic and functional validation studies.

Introduction: Brugada syndrome (BrS) is an inherited arrhythmia associated with an increased risk of sudden cardiac death. Although traditionally regarded as a primary cardiac channelopathy, pathogenic variants in SCN5A account for only 20%–30% of clinically diagnosed cases, leaving most patients genetically unresolved. Emerging evidence suggests that structural cardiac genes may also contribute to BrS susceptibility. We investigated the genetic basis of BrS in a consanguineous Lebanese family with three affected brothers. Methods and Results: Whole‐exome sequencing was performed in all affected individuals, followed by variant calling, annotation, and phenotype‐driven prioritization using Franklin (Genoox). Candidate variants were evaluated according to allele frequency, inheritance model, segregation, and ACMG/AMP classification. Evolutionary conservation, AlphaMissense prediction, protein domain annotation, and structural modeling were performed to assess the potential functional impact of the prioritized variant. Whole‐exome sequencing identified a rare homozygous CSRP3 missense variant (NM_003476.5:c.56 A > G; p.His19Arg) shared by all three affected siblings. Following exome‐wide filtering under a recessive inheritance model, CSRP3 represented the only rare homozygous coding variant, while no pathogenic or likely pathogenic variants were identified in established Brugada syndrome‐associated genes. The variant was absent from public population databases and an internal cohort of Lebanese exomes. His19 was highly conserved across vertebrate species, AlphaMissense classified the variant as likely pathogenic (score = 0.942), and structural modeling predicted alterations within the N‐terminal LIM domain that may affect protein stability and local residue interactions. Conclusions: Our findings nominate CSRP3 as a candidate susceptibility gene for Brugada syndrome and support the emerging role of structural cardiac genes in inherited arrhythmia syndromes. Although functional validation is required to establish causality, this study highlights the value of whole‐exome sequencing in consanguineous and underrepresented populations for identifying rare candidate variants contributing to BrS susceptibility.

The prevalence of lung cancer is increasing due to different risk factors with lower survival rate. Lung cancer complexity exhibits in its metastasizing ability to brain, bones, and adrenal glands. Therefore, despite the advancement of the field, the entire extent of the genetic variations associated with lung metastasis is still elusive. Patients with lung cancer metastasis show decreased effectiveness or resistance towards the available conventional drugs. In the present article, we used Genomic Data Commons (GDC) to explore the primary lung cancer genes with higher tendency to cause metastasis and aim to investigate the compatible drugs. Based on RNA-seq analysis, TFF2 and REG4 were the top two upregulated differentially expressed genes that we investigated in more details for its affinity with Gefitinib - a first generation FDA approved tyrosine kinase inhibitor drug on these two genes. Molecular docking analysis revealed that these two genes show lower binding affinity to Gefitinib, making it less effective for patients with mutation in these genes compared to patients without mutation. We believe our findings would provide better understanding of the primary mutated genes that could lead to lung cancer metastasizing to other organs and effective drug options in the clinical setting.