Search Results (2,136)

Background/Objectives: Prenatal exposure to famine can lead to lasting health effects through changes in DNA methylation. This study aims to evaluate the impact of prenatal exposure to the Chinses Great Famine (1959–1961) on human epigenome and the subsequent influence on blood lipids. Methods: We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and prenatal exposure to the Chinese Great Famine as well as blood lipids among eight participants exposed to famine and eight sex-matched participants (born ≤ 3 years after the famine). Genome-wide DNA methylation sites were profiled using the Illumina EPIC BeadChip, which covers 850K methylation positions. Results: After EWAS analyses, seven probes in genes C8orf31, ELAVL1, U6, GBA2, SHOX2, SLC1A4, and NPHP4 reached p < 1 × 10⁻⁵. Of these, famine exposure was associated with decreased methylation levels of a GBA2 exonic probe cg08258661 (p = 4.9 × 10⁻⁶). After false discovery rate (FDR) correction, pathway enrichment analyses for genes harboring nominally significant (p < 0.05) probes identified 44 significant pathways (q < 0.05), and 5 pathways were related to lipid metabolism. After FDR correction in each pathway, probes cg02622866 (5’UTR of ATF2, p = 1.09 × 10⁻³), cg07316730 (body of GRB2, p = 1.32 × 10⁻³), and cg01105385 (body of PIK3R1, p = 1.94 × 10⁻³) in the PI2K-Akt signaling pathway were associated with blood LDL-C (q ≤ 0.04); probes cg09180702 (3’UTR of PIGQ, p = 9.21 × 10⁻⁵, and q = 0.04) and cg01421548 (body of HS3ST4, p = 5.23 × 10⁻⁵, and q = 0.01) in the metabolism pathway were associated with blood LDL-C and HDL-C, respectively; In addition, probe cg08460387 (5’UTR of MAN1C1, p = 1.09 × 10⁻⁴, and q = 0.02) in the vesicle-mediated transport pathway was associated with log-transformed blood triglycerides. Conclusions: Through an epigenetic study of the Chinese Great Famine, we identified six novel genes involved in lipid metabolism. Full article

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Iron metabolism and chronic inflammation are two interrelated processes that significantly influence the initiation and progression of CRC. Iron is essential for cell proliferation, but its excess promotes oxidative stress and DNA damage, while inflammation driven by cytokine-regulated pathways accelerates tumourigenesis. We therefore conducted this narrative review to collate the available evidence on the link between iron homeostasis and inflammatory signalling in CRC and highlight potential diagnostic and therapeutic applications. Methods: This narrative review of preclinical and clinical studies explores the molecular and cellular pathways that connect iron regulation and inflammation to CRC. Key regulatory molecules, such as the transferrin receptor (TFRC), ferroportin (SLC40A1), ferritin (FTH/FTL), hepcidin, and IL-6, were reviewed. Additionally, we summarised the findings of transcriptomic, epigenomic, and proteomic studies. Relevant therapeutic approaches, including iron chelation, ferroptosis induction, and anti-inflammatory strategies, were also discussed. Results: Evidence suggests that CRC cells exhibit altered iron metabolism, marked by the upregulation of transferrin receptor (TFRC), downregulation of ferroportin, and dysregulated expression of ferritin. Inflammatory mediators such as IL-6 activate hepcidin and STAT3 signalling, which reinforce intracellular iron retention and oxidative stress. Increased immune evasion, epithelial proliferation, and genomic instability appear to be linked to the interaction between inflammation and iron metabolism. Other promising biomarkers include ferritin, hepcidin, and composite gene expression signatures; however, their clinical application remains limited. Although several preclinical studies support the use of targeted iron therapies and combination approaches with anti-inflammatory agents or immunotherapy, there is a lack of comprehensive clinical validation confirming their efficacy and safety in humans. Conclusion: Although preclinical studies suggest that iron metabolism and inflammatory signalling form an interconnected axis closely linked to CRC, translating this pathway into reliable clinical biomarkers and effective therapeutic strategies remains a significant challenge. Future biomarker-guided clinical trials are essential to determine the clinical relevance and to establish precision medicine strategies targeting the iron–inflammation crosstalk in CRC. Full article

Background: Colorectal cancer is the third most diagnosed cancer and a leading cause of cancer-related deaths worldwide. Early detection significantly improves patient outcomes, yet many cases are identified only at late stages. The high molecular and genetic heterogeneity of colorectal cancer presents major challenges in accurate diagnosis, prognosis, and therapeutic stratification. Recent advances in gene expression profiling offer new opportunities to discover genes that play a role in colorectal cancer carcinogenesis and may contribute to early diagnosis, prognosis prediction, and the identification of novel therapeutic targets. Methods: This study involved 142 samples: 84 primary tumor samples, 27 liver metastases, and 31 adjacent non-tumor tissues serving as controls. RNA sequencing was performed on a subset of tissues (12 liver metastases and 3 adjacent non-tumor tissues) using a targeted RNA panel covering 395 cancer-related genes. Data processing and differential gene expression analysis were carried out using the DRAGEN RNA and DRAGEN Differential Expression tools. The expression of six genes involved in hypoxia and epithelial-to-mesenchymal transition (EMT) pathways (SLC16A3, ANXA2, P4HA1, SPP1, KRT19, and LGALS3) identified as significantly differentially expressed was validated across the whole cohort via quantitative real-time PCR. The relative expression levels were determined using the ΔΔct method and log2FC, and compared between different groups based on the sample type; clinical parameters; and mutational status of the genes KRAS, PIK3CA, APC, SMAD4, and TP53. Results: Our results suggest that the expression of all the validated genes is significantly altered in metastases compared to non-tumor control samples (p < 0.05). The most pronounced change occurred for the genes P4HA1 and SPP1, whose expression was significantly increased in metastases compared to non-tumor and primary tumor samples, as well as between clinical stages of CRC (p < 0.001). Furthermore, all genes, except for LGALS3, exhibited significantly altered expression between non-tumor samples and samples in stage I of the disease, suggesting that they play a role in the early stages of carcinogenesis (p < 0.05). Additionally, the results suggest the mutational status of the KRAS gene did not significantly affect the expression of any of the validated genes, indicating that these genes are not involved in the carcinogenesis of KRAS-mutated CRC. Conclusions: Based on our results, the genes P4HA1 and SPP1 appear to play a role in the progression and metastasis of colorectal cancer and are candidate genes for further investigation as potential biomarkers in CRC. Full article

Analysis of selection signatures in the genomes of farm animals enables the detection of genomic regions affected by selection and contributes to the identification of genes underlying adaptive and productive traits. This research aimed to identify loci under selection pressure and to detect candidate genes in Dzhalgin Merino sheep by performing a comparative genomic analysis with the related Australian Merino and Rambouillet breeds. A total of 293 animals were included in the analysis, comprising Dzhalgin Merino (n = 53), Australian Merino (n = 50), Australian Industry Merino (n = 88), and Rambouillet (n = 102). Whole-genome SNP genotyping data for Dzhalgin Merino were generated within this study, while data for Australian Merino, Australian Industry Merino, and Rambouillet were obtained from the SheepHapMap project. For the purposes of analysis, Australian Merino and Australian Industry Merino were combined into a single group (n = 138). To enhance the reliability of the results, three independent methods were employed to detect selection signatures: the fixation index (FST), analysis of linkage disequilibrium variation (varLD), and the cross-population number of segregating sites by length (xp-nSL). The study showed that Dzhalgin Merino have unique genetic signatures potentially associated with adaptation and productivity, which opens up new opportunities for their selection. The identified genes can become the basis for developing new breeding programs aimed at improving both the productive qualities and the adaptive abilities of the breed. Further research should be aimed at a detailed investigation of gene structure within loci under selection pressure and at clarifying the mechanisms by which these genes influence animal phenotypes. A total of 185 genes were identified within genomic regions exhibiting selection signatures. Among these, particular attention was given to EPHA6, MLLT3, ROBO1, KIAA0753, MED31, SLC13A5, and ELAVL4, which are involved in biological processes such as growth, development, and reproduction. The identified genes represent potential targets for breeding programs aimed at increasing productivity and adaptive capacity of the breed. Full article

The wild yak (Bos mutus) is a flagship species on the Qinghai–Tibet Plateau, possessing significant ecological functions and conservation value. Using single-nucleotide polymorphism markers from whole-genome resequencing, we systematically analyzed golden wild yak (n = 37), common wild yak (n = 106), and domestic yak (Bos grunniens) (n = 20) to characterize the population genetic structure and adaptive selection signals in the golden wild yak. Genetic diversity analyses revealed that the golden wild yak had the lowest nucleotide diversity (π = 0.00148) and the highest inbreeding coefficient (F_Hom = 0.043). Population structure analyses integrating principal component analysis, phylogenetic tree, and ancestral component clustering indicated that the golden wild yak formed a relatively independent evolutionary lineage. However, its genetic differentiation from sympatric common wild yak population was limited (fixation index = 0.031). Selective sweep analysis identified a set of candidate positively selected genes in the golden wild yak genome associated with key traits and physiological functions, including coat color (TYRP1), hypoxia adaptation (MYH11, POLQ), reproductive function (SLC9C1, SPAG16, CFAP97D1), and immune response (CASP8, PGGT1B, BIRC6). Overall, our study reveals a distinct genetic background and selection signatures in the golden wild yak and provides genomic insights to inform the conservation and management of the wild yak. Full article

Background/Objectives: Orofacial clefts (OFCs) are among the most common birth defects globally, sometimes exacerbated by adverse drug reactions (ADRs) from corticosteroids and antiepileptics. Comprehending the pharmacogenomic and pharmacogenetic elements that lead to ADRs is essential for enhancing precision medicine and clinical outcomes. This study examines rare genetic variants in drug-metabolizing and drug-transporting genes among Ghanaian and Nigerian families with a history of OFCs, intending to assess their pathogenicity and functional implications. Methods: We recruited 104 Ghanaian families and 26 Nigerian families, generating whole-genome sequencing (WGS) data from 390 individuals (130 case-parent trios). DNA isolated from saliva and buccal swab samples underwent WGS, and subsequent WGS data were analyzed through extensive bioinformatics analyses. Variants were called and annotated using the GATK workflow. The HOPE in silico modeling tool evaluated the structural impact of genetic variants on encoded proteins, while molecular docking using PyRx examined alterations in ligand binding affinity. Results: Our study revealed pathogenic variants in vital genes associated with drug metabolism and transport, specifically CYP1A2, CYP2C18, CYP27A1, CYP2B6, SLC6A2, and ABCC3. Structural modeling research demonstrated substantial size, charge, conformation, and hydrophobicity variations between wildtype and mutant proteins. Variants positioned near conserved regions or within functional domains were anticipated to be deleterious, potentially compromising protein function and ligand interactions. Molecular docking studies verified changes in binding affinities between wildtype and mutant proteins for common ligands. The identified variations were linked to the metabolism of frequently used pharmaceuticals in Africa, such as caffeine, ketoconazole, efavirenz, carbamazepine, and artemether. Conclusions: These findings highlight the need for pharmacogenetic screening to inform personalized medicine, diminish ADRs, and enhance the clinical care of OFCs in Sub-Saharan Africa. Full article

Background: Developmental and Epileptic Encephalopathy (DEE) is a severe and heterogeneous neurological disorder in infancy/early childhood. DEE’s genetic and phenotypic variability complicates diagnosis and treatment. This retrospective study aimed to identify genetic variants and explore genotype–phenotype correlations in children with DEE using a targeted epilepsy gene panel (TGP) and Whole Exome Sequencing (WES). Patients and Methods: Medical records of children who underwent custom-designed 55-gene TGP and WES were reviewed. The diagnostic yield of each method was determined based on the detection of pathogenic (P) and likely pathogenic (LP) variants. Results: A total of 129 patients (66 males, 63 females) underwent TGP, which identified P/LP variants in 29 cases (22.48%). Variants were detected in SCN1A, KCNQ2, STXBP1, CDKL5, PCDH19, PLCB1, WWOX, SCN2A, FGF12, HCN1, SCN8A, and SLC35A2. WES further identified several variants in children with West syndrome. A TSC1 variant was detected in a patient without cutaneous stigmata of tuberous sclerosis complex. The NALCN variant in a patient was linked to Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies 1. A CTBP1 variant associated with extremely rare Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome was detected in another patient. A PIEZO2 variant—associated with Marden–Walker syndrome—was found in a child with Early Infantile Developmental and Epileptic Encephalopathy. Conclusions: These findings highlight the extensive genetic heterogeneity and phenotypic variability of DEE. WES demonstrates substantial value in identifying novel gene-disease associations and may be considered as a first-tier diagnostic tool in epilepsy and DEE. Full article

Vitamin D deficiency is highly prevalent in the Middle East despite abundant sunlight; however, most genetic studies have focused on common variants in Europeans only. We analyzed whole-genome sequences from 13,808 Qatar Biobank participants, evaluating rare variants (minor allele frequency 0.01–0.0001) for associations with serum 25-hydroxyvitamin D (25(OH)D) levels and deficiency risk (≤20 ng/mL) in independent discovery (n = 5885) and replication (n = 7767) cohorts, followed by meta-analyses. In quantitative analyses, the discovery cohort identified 41 genome-wide significant signals, including CD36 rs192198195 (p = 2.48 × 10⁻⁸), and replication found 46, including SLC16A7 rs889439631 (p = 2.19 × 10⁻⁸), implicating lipid metabolism pathways. In binary analyses, replication revealed POTEB3 rs2605913 (p = 2.8 × 10⁻⁸), while meta-analysis (n = 13,652) uncovered SLC25A37 rs952825245 (p = 5.15 × 10⁻¹²), a locus associated with cancer and vitamin D signaling. Rare-variant polygenic scores derived from discovery significantly predicted continuous (R² = 0.146, p = 9.08 × 10⁻¹²) and binary traits (AUC = 0.548, OR = 0.99, p = 9.22 × 10⁻⁶) in replication. This first rare-variant GWAS of vitamin D in Middle Easterners identifies novel loci and pathways, underscores the contribution of ancestry-specific rare alleles, and supports integrating rare and common variants to guide precision management in high-burden populations. Full article

(1) Background: IgA nephropathy (IgAN) is a leading cause of chronic kidney disease worldwide. Despite its prevalence, the molecular mechanisms of IgAN remain poorly understood, partly due to limited research scale. Identifying key genes involved in IgAN’s pathogenesis is critical for novel diagnostic and therapeutic strategies. (2) Methods: We identified differentially expressed genes (DEGs) by analyzing public datasets from the Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to elucidate the biological roles of DEGs. Hub genes were screened using weighted gene co-expression network analysis combined with machine learning algorithms. Immune infiltration analysis was conducted to explore associations between hub genes and immune cell profiles. The hub genes were validated using receiver operating characteristic curves and area under the curve. (3) Results: We identified 165 DEGs associated with IgAN and revealed pathways such as IL-17 signaling and complement and coagulation cascades, and biological processes including response to xenobiotic stimuli. Four hub genes were screened: three downregulated (FOSB, SLC19A2, PER1) and one upregulated (SOX17). The AUC values for identifying IgAN in the training and testing set ranged from 0.956 to 0.995. Immune infiltration analysis indicated that hub gene expression correlated with immune cell abundance, suggesting their involvement in IgAN’s immune pathogenesis. (4) Conclusion: This study identifies FOSB, SLC19A2, PER1, and SOX17 as novel hub genes with high diagnostic accuracy for IgAN. These genes, linked to immune-related pathways such as IL-17 signaling and complement activation, offer promising targets for diagnostic development and therapeutic intervention, enhancing our understanding of IgAN’s molecular and immune mechanisms. Full article

Chronic hepatitis C (CHC) is linked to iron overload, which significantly correlates with liver fibrosis. This study aimed to assess whether genetic polymorphisms related to iron metabolism are associated with fibrosis severity, predict improvement in fibrosis after HCV clearance with direct-acting antivirals (DAAs) and influence iron-related metabolic markers before treatment. A total of 329 CHC patients were included, 134 of whom received DAAs therapy. Liver fibrosis was assessed using transient elastography (FibroScan), and biochemical parameters were measured using standard methods. Eighteen genetic polymorphisms within five iron metabolism-related genes were analyzed using PCR-RFLP, endpoint genotyping, or next-generation sequencing (NGS). Before DAA treatment, patients with severe fibrosis showed higher levels of serum iron (Fe), total iron-binding capacity (TIBC), and ferritin (Ft). SLC40A1 rs1439816_GG was associated with an increased risk of severe fibrosis compared with GC or CC genotypes. SLC40A1 rs11568351_GC genotype was linked to a higher likelihood of remaining cirrhotic after HCV clearance. Elevated iron parameters were observed in carriers HFE C282Y_CY, TF IVS 11 G>A, and BMP2 570 A>T. Overall, polymorphisms in iron metabolism genes may influence both the severity of liver fibrosis prior to treatment, its regression after DAA therapy and the regulation of iron metabolism in CHC patients. Full article

Background: Suicide attempts often co-occur with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCH). Although impairments of the serotonin (5-HT) system have been associated with suicide attempts, it remains unclear whether these alterations reflect suicidal behavior or are confounded by underlying psychiatric diagnosis. This study used a genotype-informed dynamic model of the 5-HT presynapse to disentangle the effects of suicide attempts and psychiatric diagnosis. Methods: We applied a personalized dynamic model of the 5-HT presynapse to 392 psychiatric patients (with BD, MDD, or SCH), categorized by suicide attempt status, and 140 unaffected individuals. The model incorporated five variants across TPH2, SLC6A4, and MAOA genes simulating individual-specific concentration changes of five 5-HT-related molecular species. Model outputs were summarized by six statistical measures (mean, median, maximum, standard deviation, skewness, and kurtosis) and compared across groups. Results: No significant differences were found across groups defined by suicide attempt status and unaffected individuals. However, diagnosis significantly influenced 5-hydroxyindoleacetic acid (5-HIAA) mean, median, maximum, and standard deviation (all p < 0.05). BD patients had lower 5-HIAA levels than SCH patients (mean: p = 0.013; median: p = 0.013; maximum: p = 0.014; standard deviation: p = 0.014). MDD patients also showed lower 5-HIAA levels than SCH patients for the same measures, with differences approaching significance. No significant difference was observed between BD and MDD patients. A diagnosis-by-suicide attempt status interaction was observed for 5-HIAA skewness (p = 0.013). Conclusions: Model-derived 5-HT profiles were shaped primarily by diagnosis, while temporal dynamics of 5-HIAA, rather than its absolute levels, was associated with suicide attempt status. Thus, personalized dynamic modeling incorporating genetic variants may aid in detecting subtle molecular signatures across diagnoses and suicidal behavior. Full article

Cerebral ischemia/reperfusion (I/R) injury is a devastating neurological disorder with limited treatment options. Emerging evidence suggests that the N6-methyladenosine (m6A) modification and its regulatory factors play pivotal roles in the pathophysiology of I/R. This study aimed to elucidate the function of METTL3-mediated m6A modification of the long non-coding RNA (lncRNA) AU020206 in ferroptosis during cerebral I/R injury and to identify potential molecular targets for neuroprotection. A murine model of middle cerebral artery occlusion/reperfusion (MCAO/R) and N2a cells subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) were established to assess m6A levels and ferroptosis-related changes. Effects of METTL3 overexpression and lncRNA-AU020206 silencing on neuronal apoptosis, inflammation, and ferroptosis were investigated in vitro and in vivo. The interaction between lncRNA-AU020206 and YTHDC2 and the resulting regulation of SLC7A11 mRNA stability and GPX4 expression were evaluated using molecular and biochemical assays. Both MCAO/R mice and OGD/R-treated N2a cells exhibited decreased m6A levels and upregulation of lncRNA-AU020206 accompanied by enhanced ferroptosis. METTL3 overexpression increased the m6A modification of AU020206, promoting its degradation and attenuating neuronal injury, whereas silencing AU020206 or overexpressing YTHDC2 decreased SLC7A11 mRNA stability and enhanced ferroptosis. Restoring the expression of SLC7A11/GPX4 can enhance cell viability, alleviate neuronal apoptosis, and reduce Fe²⁺ overload. Disruption of the METTL3–AU020206–YTHDC2 axis abolished these neuroprotective effects. METTL3-mediated m6A modification of lncRNA-AU020206 restrained ferroptosis and neuronal injury in cerebral I/R by maintaining the stability of the SLC7A11/GPX4 axis via interactions with YTHDC2. Targeting this epitranscriptomic signalling pathway may represent a promising therapeutic strategy for the treatment of ischemic stroke and related neurological disorders. Full article

Background/Objectives: Metal transporter gene SLC39A8 and single nucleotide polymorphism (SNP) rs13107325 are associated with risk factors for atherosclerosis and cardiovascular disease (CVD). However, it is unclear how dietary manganese intake impacts CVD risk factors. The aim of this study was to use the UK Biobank population cohort (276,436 participants, Caucasian genetic ancestry, no genetic kinship) to investigate whether rs13107325 and dietary manganese are associated with CVD risk. Methods: A cross-sectional design and quantile (median) regression was used to determine associations of rs13107325 and dietary manganese intake with indicators of CVD risk. Results: SNP rs13107325 was associated with CVD risk factors, including greater body mass index (BMI) (beta ± SE per rs13107325 allele = 0.283 ± 0.0392, false discovery rate (FDR) < 10⁻¹⁰) and triglycerides (beta ± SE = 0.0308 ± 0.00761, FDR < 0.001) and reduced high density lipoprotein (HDL) (beta ± SE = −0.0298 ± 0.00343, FDR < 10⁻¹⁵). SNP rs13107325 was also associated with lower systolic (beta ± SE = −0.601 ± 0.172, FDR < 10⁻³) and diastolic blood pressure (beta ± SE = −0.531 ± 0.100, FDR < 10⁻⁵). Dietary manganese intake was positively correlated with measures of favorable cardiovascular health, such as lower BMI (beta ± SE per mg dietary manganese = −0.531 ± 0.0118, FDR < 10⁻³⁰⁰), reduced triglycerides (beta ± SE = −0.0451 ± 0.00229, FDR < 10⁻⁵⁰), increased HDL (beta ± SE = 0.00958 ± 0.00103, FDR < 10⁻¹⁵), and lower blood pressure (systolic beta ± SE = −0.529 ± 0.0520, FDR < 10⁻²⁰; diastolic beta ± SE = −0.562 ± 0.0302, FDR < 10⁻⁵⁰). Conclusions: The favorable associations of dietary manganese opposed many deleterious trends associated with rs13107325. Increased dietary manganese may promote cardiovascular health and offset many risks to cardiovascular health linked to SNP rs13107325. Full article

Background: Despite advances in gene-targeted and immunotherapies, many aggressive cancers—including glioblastoma and triple-negative breast cancer—remain refractory to treatment. Mounting evidence implicates metabolic reprogramming, especially dysregulation of glucose and glutamine metabolism, as a core hallmark of tumor progression. Natural compounds with metabolic-modulatory effects have emerged as promising adjuncts in oncology. Research Question and Objectives: This review investigates the following question: How can metabolic-targeted therapies—particularly those modulating the Warburg effect and glutamine metabolism—improve cancer treatment outcomes, and what role do natural compounds play in this strategy? The objectives were to (1) evaluate the therapeutic potential of metabolic interventions targeting glucose and glutamine metabolism, (2) assess natural compounds with metabolic regulatory activity, (3) examine integration of metabolic-targeted therapies with conventional treatments, and (4) identify metabolic vulnerabilities in resistant malignancies. Methods: A qualitative systematic review (QualSR) was conducted following PRISMA guidelines. A total of 87 peer-reviewed studies published between 2000 and 2024 were included. Inclusion criteria required clearly defined mechanistic or clinical endpoints and, for clinical trials, sample sizes ≥ 30. Data extraction focused on tumor response, survival, metabolic modulation, and safety profiles. Results: Curcumin significantly reduced serum TNF-α and IL-6 (both p = 0.001) and improved antioxidant capacity (p = 0.001). EGCG downregulated ERα (p = 0.002) and upregulated tumor suppressors p53 and p21 (p = 0.001, p = 0.02). High-dose intravenous vitamin C combined with chemoradiotherapy yielded a 44.4% pathologic complete response rate in rectal cancer. Berberine suppressed Akt/mTOR signaling and glutamine transporter SLC1A5 across tumor types (q < 10⁻¹⁰). However, poor bioavailability (e.g., EGCG t½ = 3.4 ± 0.3 h) and systemic toxicity limit their standalone clinical application. Conclusions: Metabolic-targeted therapies—particularly natural compounds acting on glucose and glutamine pathways—offer a viable adjunct to standard cancer therapies. Clinical translation will require biomarker-driven patient stratification, improved delivery systems, and combination trials to optimize the therapeutic impact in treatment-resistant cancers. Full article

Objective: This study aims to explore the mechanism of regulated cell death-related genes in the development of endometrial carcinoma. Methods: Endometrial carcinoma-related datasets were yielded via the Cancer Genome Atlas and Gene Expression Omnibus databases, and regulated cell death-related genes were extracted from the literature. Differential expression analysis, weighted gene co-expression network analysis, and protein interaction analysis were performed to identify critical regulated cell death-related genes. Gene set enrichment analysis was used to identify the functional pathways involved in these critical genes. Afterward, the best clustering approach for tumor samples was yielded via consensus clustering analysis, and nomogram prediction models were built. Shiny Methylation Analysis Resource Tool was used to compare the expression levels of CpG methylation probes for critical genes between tumor and normal samples. Spearman correlation analysis was conducted to investigate the relationship between critical genes and various immune features. Eventually, immuno-infiltrative analysis was implemented, and potential therapeutic agents were screened targeting critical genes. The data were analyzed and visualized by R software using different packages. In addition, the expressions of critical genes were validated by quantitative real-time polymerase chain reaction and immunochemistry. Results: Four critical genes, namely GBP2, SLC11A1, P2RX7, and HCLS1, were identified, and they were involved in various functional pathways such as leukocyte-mediated cytotoxicity. There were substantial differences in CpG methylation in GBP2, SLC11A1, and HCLS1 between tumor and normal samples. As for immune features, all critical genes were positively connected with immunosuppressive factors such as TIGIT and most HLA molecules in endometrial carcinoma. The critical genes high/low expression groups of tumor samples showed different immune responses towards PD-1, PD-L1, and CTLA-4 immunotherapy. The infiltration of 24 immune cells, such as effector memory CD8⁺ T cells, was notably different between tumor and normal samples. Based on sensitivity analysis of chemotherapeutic agents, we found the highest positive correlation between SLC11A1 and “BI.2536” and the strongest passive correlation of HCLS1 and GBP2 with “Ribociclib”, as well as P2RX7 with “BMS.754807”. Quantitative real-time polymerase chain reaction suggested that the expression trends of GBP2, P2RX7, and HCLS1 were consistent with the results of bioinformatic analysis. Conclusions: Regulated cell death-related genes (GBP2, SLC11A1, P2RX7, and HCLS1) may play a role in endometrial carcinoma development, which can provide new ideas for the treatment and prognosis prediction of this disease. Full article