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.
In-hospital cardiac arrest (IHCA) from non-cardiac causes is a life-threatening condition characterized by high mortality and complex etiology. Despite advances in critical care monitoring, effective early warning systems remain lacking due to challenges in balancing sensitivity and specificity within imbalanced clinical data and the interpretability of machine learning models remains poorly defined. We developed and evaluated six machine learning algorithms using data from 43,618 ICU patients in the MIMIC-IV database. Model performance was assessed through multiple metrics, and SHapley Additive exPlanations (SHAP) analysis was employed for model interpretability. Decision curve analysis was performed to evaluate clinical utility. Distinct performance trade-offs were identified across models. XGBoost achieved optimal discriminative ability (AUC = 0.730, 95
Gastric cancer is a prevalent tumor and ranks fourth in terms of cancer-related mortality worldwide. This study investigated the impact of telomere dysregulation on available genome-wide expression profiles comprising gastric cancer subtypes. Therefore, telomere-related signatures were obtained from the molecular signatures database and examined using gene set-based pathway activation scoring analysis in the collected mRNA expression profiles. Notably, most telomere maintenance processes, such as regulation of telomerase enzyme assembly and activity, regulation of telomere synthesis and capping, telomere organization, telomere elongation, and telomere length maintenance, were found to be enriched and dysregulated in an intestinal subtype of gastric tumors. Strikingly, telomere gene sets or overlapped genes among telomere signatures are also highly activated in intestinal subtype gastric tumors. Gene set enrichment analysis (GSEA) for this gene set also reconfirmed that these genes are associated with the tumorigenesis of this subtype of tumor. Furthermore, the telomere maintenance dysregulation processes vital genes such as ACD shelterin complex subunit and telomerase recruitment factor (ACD), protection of telomeres 1 (POT1), regulator of telomere elongation helicase 1 (RTEL1), telomeric repeat binding factor 1 (TERF1), telomeric repeat binding factor 2 (TERF2), and telomerase reverse transcriptase (TERT) expressions were further validated in the clinicopathological features like primary tumors, histopathological type, grade, and stage in TCGA stomach adenocarcinoma (STAD) profile. Moreover, overall survival curve plots reaffirmed the correlation between these gene expressions and poor survival in patient cohorts with intestinal subtypes of stomach cancer. Thus, the current results show that telomere maintenance pathways dysregulation exists and is potentially involved in the intestinal subtype of gastric carcinogenesis. Based on this finding, these genes are potential diagnosis and prognosis biomarkers for targeted therapy approaches of this subtype of gastric cancer treatment.
Extracellular vesicles (EVs) are lipid bilayer nanoparticles secreted by almost all cell types, serving as vital mediators of intercellular communication by transporting bioactive cargos, including proteins, lipids, and nucleic acids. This review summarizes the emerging role of EVs as pivotal carriers in cancer epigenetic regulation, focusing on their functions in cancer pathogenesis through the delivery of non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as well as the modulation of DNA methylation and histone modifications. Drawing on evidence from various malignancies (including osteosarcoma, breast cancer, gastric cancer, hepatocellular carcinoma, cervical cancer, lung cancer, pancreatic cancer, colorectal cancer, bladder cancer, and esophageal squamous cell carcinoma), we systematically elucidate how tumor- or matrix-derived EVs promote tumor progression by delivering specific epigenetic regulators (e.g., NORAD, miR-3190, and circ_0064516). These EV-encapsulated molecules can inhibit tumor suppressors, activate oncogenic pathways (such as PI3K/AKT and Wnt/β-catenin), and promote epithelial-mesenchymal transition, angiogenesis, immune evasion, and metastasis. Furthermore, EVs reshape the epigenetic landscape of the tumor microenvironment by inducing genomic DNA hypomethylation (e.g., LINE-1) and altering histone modifications. Finally, we discuss the potential of EV-associated epigenetic molecules as diagnostic biomarkers and therapeutic targets, underscoring the clinical significance of EVs as key information carriers in oncology.
Cuproptosis, a novel copper-dependent form of cell death, induces proteotoxic stress by targeting lipoylated mitochondrial proteins, offering a new strategy to overcome cancer therapy resistance. ferredoxin 1 (FDX1) is the core regulator of cuproptosis, and its expression exhibits significant heterogeneity across cancer types. This review systematically summarizes the multi-layered regulatory network governing FDX1, including protein interactions, non-coding RNA targeting, and epigenetic modifications. Targeting strategies are categorized based on expression differences: developing inhibitors to block its pro-tumorigenic effects in cancers with high FDX1 expression, or activating FDX1 expression/function to induce cuproptosis in cancers with low FDX1 expression. While novel nanomaterial-based combination therapies show therapeutic potential, key challenges hindering clinical translation include the lack of FDX1-specific drugs, incomplete understanding of its dynamic regulatory network, and unclear feedback mechanisms. This review provides a theoretical foundation and translational directions for cancer therapy targeting the FDX1-cuproptosis axis.
Hepatocellular carcinoma (HCC) is one of the most highly aggressive and fatal malignancies. It ranks as the sixth most common tumor in the world and, more importantly, it occupies the third position among cancer-related deaths. Centella asiatica is a medicinal plant widely pharmacologically potent which may include anti-inflammatory, anticancer, hepatoprotective as well as wound healing activity. Increasing evidence supports cross-kingdom regulation for plant-origin microRNAs (miRNAs), delivered into host cells through dietary intake to regulate gene expression levels involved in pharmacological actions from medicinal plants. An in silico homologous miRNA screening method was applied to identify potential Centella asiatica miRNAs targeting HCC genes. Homologous miRNA sequences were first identified from the Centella asiatica genome with BLASTN, and their secondary structures were predicted with MFold server. Putative human targets were then predicted using psRNATarget and only those retained that could be cross-referenced with known HCC-associated genes. These targets were subjected to Gene Ontology and KEGG pathway analysis in Enrichr and DAVID, respectively. Protein-protein interaction (PPI) networks were then constructed in Cytoscape for hub gene identification using cytoNCA while survival and expression analyses were implemented in GEPIA2.49 C.asiatica miRNAs were identified with 63 target genes overlapping the HCC-associated gene set. CDKN1A, IRS1, MAPK14, SSB, and TARDBP were found as hub genes from PPI network analysis among the targets. Further filtering of these hubs through survival analysis revealed them as prognostic hubs possibly regulated by cai-miR393a and cai-miR156a. This is the first comprehensive study to predict that Centella asiatica-derived miRNA particularly cai-miR393a and cai-miR156a may play a role in HCC by targeting SSB and TARDBP. Therefore, results of the present study add a novel cross-kingdom regulatory mechanism and place Centella asiatica miRNAs as potential candidates for translational developments in HCC therapy.
Infection with hepatitis B virus (HBV) is a global health problem, causing diseases such as acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Numerous studies in the literature have demonstrated hepatitis B surface antigen (HBsAg) as the first virological marker of HBV infection, and that serum HBsAg levels are reported to be an important criterion for the diagnosis and management of HBV infection. Therefore, the sensitive and selective detection of HBsAg is critical for the early diagnosis of hepatitis B and for the management of the diseases associated with HBV infection. Electrochemical immunosensors play an important role in the early diagnosis of infection with hepatitis B virus since they are rapid, easy-to-use, and reliable diagnostic tools with a possibility of on-site detection. Besides, they might have superior performance in terms of multiple analytical parameters compared to more commonly used alternatives in the clinic, including ELISA. Herein, we review the reported success and potential of electrochemical biosensors for the detection of HBsAg in the early diagnosis and monitoring of hepatitis B virus infection, and provide a brief overview for future studies, with the ultimate aim of directing more research focus into this topic.
The present study discovers differentially expressed genes that have a particular impact on gastric cancer. The Gene Expression Omnibus was used to extract the transcriptome profiles of gastric cancer and noncancerous tissue samples to identify these genes. Differentially expressed genes were obtained utilizing the GEO2R tool. Genes frequently observed among upregulated genes in these profiles were deemed to represent a gastric cancer gene set. The ontological function of the gastric cancer gene set was then investigated using the Molecular Signatures Database, and the effects of gene mutations on the gene expression profile of stomach cancer were studied using the cBioPortal database. OncoPrint results had 33 amplified genes in over 5
The genome, which is an organism’s complete genetic blueprint, consists of a dynamic mixture of unique and repetitive DNA sequences that are continuously evolving, making the human genome a prime example of this complexity. Repetitive sequences emerge through mechanisms such as replication slippage, transpositions, and unequal recombination, whereas non-repetitive sequences evolve through point mutations, insertions and deletions, segmental duplication errors, and horizontal gene transfers. This review explores the evolution of polymeric nucleic acids, genome proliferation and homeostasis, and the various mechanisms that drive genomic diversity. It further highlights the occurrence and biological significance of DNA repeats across different domains of life. In addition, the review critically evaluates the impact of these sequences on genome instability, regulatory processes, and their involvement in human diseases. The concluding sections integrate current evidence on the contribution of repetitive elements to evolution, focusing on the interplay between genetic and epigenetic mechanisms that govern their fate, and emphasize how this knowledge is crucial for advancing genome function research and personalized medicine.
Psoriasis, a prevalent immune-mediated inflammatory skin disease, has a complex pathogenesis involving genetic predisposition, immune system dysregulation, and environmental triggers. Despite its prevalence, treatment options remain limited. Tripteaser wilfordii Hook (TWH), a traditional Chinese medicine, has shown potential in treating psoriasis, and recent studies suggest that its therapeutic effects may be related to its ability to modulate the immune system and microecological balance, similar to how medical ozone therapy has been found to influence immune regulation and inflammation in psoriasis. This study aimed to explore the targets and pathways of psoriasis treatment, focusing on symptom relief, prevention of disease progression, improvement of quality of life, and the integration of psychological health. TWH compound preparation against psoriasis using network pharmacology and molecular dynamics. The methodology involved screening active compounds of TWH from the TCMSP database and retrieving psoriasis-associated genes from multiple sources. Key hub genes were identified through topological analysis of the constructed protein–protein interaction (PPI) network with Cytoscape 3.8.2. Potential mechanisms were explored via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The interaction between compounds and proteins was predicted using molecular docking and molecular dynamics simulations with Auto Dock Vina and Chimera 1.15. We identified 15 active compounds from TWH, along with 88 psoriasis-related targets. Network analysis identified key hubs, including AKT1, ESR1, TP53, STAT3, TNF, BCL2, JUN, HSP90AA1, CASP3, and RELA. Pathway enrichment analysis revealed mechanisms primarily involving inflammation and immune responses. SwissADME profiling nominated Zhebeiresinol, Kaempferol, and 5,8-Dihydroxy-7-(4-hydroxy-5- methylcoumarin-3-yl) coumarin as promising lead candidates. Molecular docking and dynamics simulations confirmed that 5,8-Dihydroxy-7-(4-hydroxy-5-methylcoumarin-3-yl) coumarin and kaempferol bind stably to the STAT3 protein. This binding is primarily driven by van der Waals forces, suggesting their potential as natural product-derived therapeutics for psoriasis. We have identified fixed-dose combinations of 5,8-Dihydroxy-7-(4-hydroxy-5- methylcoumarin-3-yl) coumarin and kaempferol as part of novel target strategies for psoriasis, which inhibit specific JAK-STAT signaling pathway simultaneously, leading to superior efficacy and the ability to counter drug resistance.
Helicobacter pylori (H. pylori) is a globally prevalent gastric pathogen with substantial genetic diversity shaped by human co-evolution. Although extensive research has been conducted on H. pylori, the mechanisms underlying its adaptation and virulence remain incompletely understood. Here, we performed a phylogenomic analysis of 1467 isolates from 26 countries by constructing a core-genome single-nucleotide polymorphism (SNP) phylogeny and analyzing population structure, revealing five major lineages with distinct regional adaptations. A genome-wide Fixation Index (Fst) analysis identified 20 highly differentiated genes, with cagE (Fst = 0.8041)—a key component of the Type IV Secretion System (T4SS)—showing the strongest signal of positive selection. We discovered a novel N792D mutation in cagE, fixed in cluster c1, particularly in North America, which may enhance immune evasion and promote persistent colonization. Bayesian Evolutionary Analysis Sampling Trees 2 (BEAST2) analysis estimated that the most recent common ancestor (tMRCA) of highly virulent H. pylori emerged around 1934 (95
The essential autophagy regulator EPG5 has been implicated in a rare but severe autosomal recessive disorder known as Vici syndrome, which is characterized by multisystem involvement, including agenesis of the corpus callosum, cataracts, immunodeficiency, cardiomyopathy, and hypopigmentation. This review systematically elucidates the dual roles of EPG5 in autophagy and endocytic trafficking, comprehensively delineates the clinical manifestations of Vici syndrome, critically evaluates current therapeutic strategies, and proposes potential approaches to improve diagnosis and treatment for this debilitating disease. Furthermore, we highlight future research directions aimed at bridging molecular mechanisms with clinical translation, which may advance our understanding of the pathogenesis of Vici syndrome.
Hepatocellular carcinoma is one of the most lethal malignancies which is a rapidly growing and aggressive cancer of the liver. It ranks as the third most common cause of cancer-related death and the sixth most common tumor. The herb Curcuma longa contains a hydrophobic polyphenol called curcumin, which possesses a diverse range of biological and pharmacological properties, including anti-inflammatory, anti-oxidant, anti-proliferative, and antiangiogenic activities. Despite these known effects, the specific molecular mechanism by which curcumin exerts its anti-cancer effects on HCC-related targets through network pharmacology has yet to be fully understood. In this study, To assess the drug-like properties and ADME characteristics of curcumin, the QikProp tool in the Maestro module of Schrödinger software was utilized. Further we identified a total of 407 potential targets that overlapped between HCC and curcumin through network pharmacology approch. To gain further insights into these targets, we conducted gene ontology, and pathway enrichment analyses using the Enrichr webserver. Additionally, we constructed a protein-protein interaction network using Cytoscape software and identified the top 10 hub nodes using the CytoNCA plugin. To validate the significance of these hub nodes, we performed survival analysis using the KM plotter database and expression analysis using the GEPIA2 database. The results obtained from Molecular Docking and Molecular dynamic simulations, conducted using the Glide module and Desmond module respectively (Schrödinger software), and identified TNF as potential target for curcumin in the treatment of HCC. Furthermore, the Prime module in the Schrödinger suite was employed to compute the free energy of binding between curcumin and the protein target, employing the MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) procedure. This analysis revealed a strong binding affinity between TNF and curcumin. Our findings not only support the anti-oncogenic role of curcumin but also shed light on the potential clinical application of curcumin in HCC therapeutics, with TNF as a promising target.
This study represents the first systematic investigation of RNA modification-related biomarkers in ICH through integrated transcriptomic and single-cell RNA sequencing analyses. Ybx1 and Igf2bp2 were identified as key RM-related biomarkers in ICH. Both Ybx1 and Igf2bp2 were enriched in synaptic signaling and translational pathways. Ybx1 exhibited dynamic, stage-specific fluctuations in microglia 1 and monocytes, while Igf2bp2 expression remained relatively stable. Predominant expression of YBX1 was observed in non-classical monocytes, whereas IGF2BP2 was primarily expressed in myeloid dendritic cells. RNA modifications play a pivotal role in regulating intracerebral hemorrhage (ICH). However, RNA modification-related genes (RMRGs) in ICH remain largely unexplored. This study aims to identify such biomarkers by integrating bulk and single-cell transcriptomic data. Single-cell and transcriptomic data related to ICH were obtained from public databases, and RMRGs were sourced from existing literature. Differentially expressed genes were identified from the GSE216607 dataset and cross-referenced with RMRGs to generate candidate genes. Protein-protein interaction networks were then employed to identify core genes. Gene expression analysis of these core genes was conducted to pinpoint biomarkers in ICH. Functional enrichment analysis followed, and the expression of biomarkers in immune cells was examined. Additionally, drug predictions were made, and single-cell analysis was performed to characterize cell types and identify key cells based on biomarker expression. Ybx1 and Igf2bp2 were identified as biomarkers, with their expression levels upregulated in ICH samples from both the GSE216607 and GSE206971 datasets. Enrichment analysis indicated that these biomarkers are associated with neuronal systems and other related pathways. Further, these biomarkers were mapped to their human homologs, YBX1 and IGF2BP2. YBX1 exhibited the highest expression in non-classical monocytes, while IGF2BP2 was predominantly expressed in myeloid dendritic cells. Additionally, 3-butylidenephthalide, lithium chloride, and cantharidin were predicted as potential therapeutic agents for ICH. Single-cell analysis revealed monocytes and microglia 1 as key cell types. Ybx1 and Igf2bp2 were identified as RM-related biomarkers in ICH, offering novel insights for ICH prevention and therapeutic strategies.
The lethal triad of acidosis, hypothermia, and coagulopathy synergistically elevates trauma, yet their genetic interdependence remains unestablished. Through bidirectional Mendelian randomization (MR) leveraging European-ancestry GWAS (acidosis, n = 618,205; hypothermia, n = 623,671; coagulopathy, n = 3,268,220), we assessed causal relationships using rigorous instrumental variables (P < 5 × 10− 5, F-statistics > 10) and sensitivity analyses (MR-Egger, weighted median, MR-PRESSO). Results demonstrated genetic independence: acidosis showed null effects on coagulopathy (OR = 0.987, 95
Alzheimer’s disease is a neurodegenerative disease that is usually detected at a late stage when it is no longer possible to treat the disease, only its symptoms; since diagnosis is currently difficult at an early stage. However, the progression of the disease can be slowed down with available treatment methods if diagnosed at an early stage. Alzheimer’s disease significantly reduces the quality of life for both the patient and their family. Amyloid beta (Aβ) protein 42 (Aβ42) is one of the main biomarkers widely used for the diagnosis of Alzheimer’s disease. Rapid, sensitive and reliable biosensors have become a focus of interest for researchers to be able to provide early-stage detection and treatment window for better therapy response. Here, we commented on electrochemical biosensors that can reliably detect Aβ42 protein in different biological/clinical samples, and demonstrated their success in the early diagnosis of Alzheimer’s disease, and addressed the need for further research on electrochemical biosensors for the early diagnosis of this disease.
Conocarpus erectus L., a traditionally important medicinal plant, is increasingly recognized as a potential source of bioactive small RNAs with therapeutic relevance. Leveraging a cross- and intra-kingdom computational framework, we identified and characterized 30 novel microRNAs (miRNAs) from the C. erectus transcriptome. These plant-derived miRNAs were predicted to target genes in both Homo sapiens and Arabidopsis thaliana, thereby offering a unique opportunity to explore conserved and species-specific molecular mechanisms. Functional enrichment of human and A. thaliana gene targets revealed significant involvement in regulatory networks controlling genome integrity, including pathways related to MAPK signaling, PI3K-Akt, insulin, and neurotrophin signaling, as well as cellular senescence. In humans, top-ranked hub genes such as CDC42, MAPK14, PIK3R1, AR, and NTRK2 were implicated in genome instability-associated conditions, including neurodegeneration and metabolic diseases. In parallel, the A. thaliana targets provided insights into conserved post-transcriptional regulatory networks and stress adaptation pathways. Notably, both organisms demonstrated miRNA influence over genes involved in DNA repair, epigenetic modulation, and signal transduction. Molecular dynamics simulations validated the structural stability of the CDC42–cer-miR1134-5p complex over a 300 ns trajectory, suggesting stable and functional RNA-RNA interactions. Collectively, our findings propose that C. erectus miRNAs act as interspecies epigenetic regulators with the potential to impact genome stability, offering promising leads for novel RNA-based therapeutics in neurodegenerative and genome instability-linked diseases.
In their recent Cell publication, Kang et al. shed light on a critical yet poorly understood aspect of cancer biology: how tumor cells preserve oncogenic extrachromosomal DNA (ecDNA). The study reveals that DNA topoisomerases frequently introduce double strand breaks into ecDNA, triggering its rapid degradation. Importantly, the authors identify a DNA damage repair pathway that counteracts this degradation by re-circularizing ecDNA. Given the potent oncogenic potential of ecDNA, these findings not only deepen our mechanistic understanding of ecDNA maintenance but also highlight promising new therapeutic targets in ecDNA-positive cancers.
Genetic constraint and population-specific variant landscapes are pivotal in evaluating drug target feasibility. Rac1, a GTPase implicated in treatment-resistant hypertension and Plasmodium falciparum invasion of red blood cells (RBCs), represents a high-priority therapeutic candidate. This study leverages genome aggregation database (gnomAD) data to analyze Rac1’s genetic profile, focusing on its dual role in host-pathogen interactions and cardiovascular pathology. We interrogated Rac1’s genetic constraint metrics (LOEUF, missense Z-scores), minor allele frequencies (MAF), and functional annotations across five global populations: African/African American (AFR), Admixed American (AMR), East Asian (EAS), Non-Finnish European (NFE), and South Asian (SAS). Variant Effect Predictor (VEP) focused on 3’/5’ untranslated regions (UTRs), complemented by ANOVA to assess population-specific variant distributions. Rac1 appears to demonstrate strong intolerance to loss-of-function mutations (LOEUF = 0.25), underscoring potential on-target toxicity risks. Population-specific MAF disparities emerged in UTRs: AFR exhibited the highest 3’ UTR mean MAF (0.0112) and maximum MAF (0.716), while 5’ UTR MAFs were uniformly low across populations (e.g., AFR = 0.0000605, NFE = 0.00000285). ANOVA revealed no significant population-dependent differences in UTR variant distributions (p-values: AFR = 0.676; AMR = 0.973; EAS = 0.967; NFE = 0.985; SAS = 0.976), supporting conserved regulatory architecture. Functional domains (e.g., GTPase-binding regions) lacked pathogenic variants, whereas non-conserved regions harbored missense polymorphisms. UTR variants clustered in transcriptionally active regions, potentially modulating Rac1’s roles in hypertension and RBC remodeling. While Rac1’s high genetic constraint signals caution for direct inhibition, UTR variants and non-essential domains may present safer therapeutic windows for modulating its activity in treatment-resistant hypertension or disrupting Plasmodium invasion. AFR-specific enrichment of high-frequency 3’ UTR variants, despite globally conserved distributions, highlights the importance of inclusive trial designs to address genetic diversity in these conditions. This study illustrates how gnomAD-driven population genetics can refine target prioritization, balancing efficacy and safety in drug discovery pipelines for infectious and cardiovascular diseases.
