Search Results (4,172)

Cellular therapy using human cardiac mesenchymal progenitor cells (hMPCs) for regenerative medicine is hindered by poor cell survival and senescence. Long non-coding RNAs (lncRNAs) are critical regulators of cellular processes, yet their role in cardiac aging remains underexplored. Here, lncRNA microarray profiling identified a novel lncRNA, XLOC_002543, upregulated in hMPCs preconditioned with cobalt protoporphyrin (CoPP), which was named CoPP-Induced and SFPQ-Associated RNA Transcript (CISAT) due to its interaction with splicing factor proline and glutamine rich (SFPQ), confirmed via RNA pull-down and immunoprecipitation. CISAT was the only highly expressed transcript among seven lnc-ANKMY1-5 variants in hMPCs, as shown by RT-PCR. Notably, CISAT expression decreased in aging/senescent hMPCs, correlating with elevated p16^INK4A, a senescence marker. Overexpression of CISAT reduced p16^INK4A levels; enhanced hMPC survival, proliferation, and migration; and increased antioxidant and anti-apoptotic protein expression, while CISAT knockdown reduced resistance to H₂O₂-induced oxidative stress. In vivo, intramyocardial transplantation of CISAT-overexpressed hMPCs in an immune-deficient murine myocardial infarction model reduced fibrosis, promoted angiogenesis, and preserved cardiac function. Mechanistically, CISAT interacts with SFPQ to regulate NRF2-mediated redox homeostasis and inhibits p38 MAPK phosphorylation, mitigating senescence and enhancing cell survival. These findings suggest that targeting CISAT to modulate redox signaling and p38 MAPK pathways in aging hMPCs could improve their therapeutic efficacy for myocardial repair in heart disease. Full article

Background: Polyploid and chromosomal copy number gains (CNGs) cells may serve as key mediators of tumor plasticity, therapeutic resistance, and clonal evolution. Despite growing interest, their biological and clinical relevance in colorectal cancer, particularly in the metastatic setting, remains poorly defined. Methods: We performed an integrated morphological, cytogenetic, and genomic analysis of metastatic colon cancer. A tissue microarray comprising 100 tumors was evaluated, of which 47 cases were fully assessable for morphology and fluorescence in situ hybridization (FISH). Polyploid nuclei and chromosomal CNGs were assessed morphologically and cytogenetically. High-resolution targeted sequencing (TruSight Oncology 500) was conducted to characterize genomic alterations. Bioinformatic analyses included Gene Ontology enrichment and Phenolyzer network modeling. Associations with clinicopathological variables and survival outcomes were explored. Results: Polyploid nuclei and/or chromosomal CNGs were identified in approximately 25% of evaluable cases. These alterations were enriched in right-sided CRCs and in older patients, suggesting a link with age-related genomic instability. Polyploid/CNG tumors did not show significant enrichment for canonical CRC driver mutations (RAS, TP53, SMAD4), although trends toward co-occurrence with BRAF mutation and mutual exclusivity with HER2 amplification were observed. Integrative bioinformatic analyses highlighted dysregulation of pathways involved in mitotic control, centrosome organization, and DNA replication stress. Conclusions: In metastatic colon cancer, the presence of genome-wide copy number gain may delineate a tumor subset with distinctive clinicopathological and molecular characteristics. Further studies are warranted to elucidate the biological significance of these features and to explore their potential implications for tumor evolution, treatment response, and clinical stratification. Full article

Background/Objective: Although most melanocytic lesions are diagnosed as benign or malignant by histopathologic evaluation, with or without the aid of immunohistochemistry, diagnosis may remain uncertain in a minority of cases. Assessment of copy number abnormalities (CNAs) may provide sufficient additional evidence to favor either a benign or malignant diagnosis in both pediatric and adult cases and in melanocytic lesions of various subtypes, including Spitzoid, mucosal, and acral. CNAs are common in melanomas, while they are rare, with few exceptions, in benign lesions. Detection of CNAs by fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA) has been well established for melanocytic lesions, with advantages and disadvantages for each. The objective of this meta-analysis was to evaluate the utility of CNA testing for the diagnosis of melanoma, across subtypes, when a lesion remains ambiguous after histopathologic and immunohistochemical assessment. In addition, the utility of CNAs to determine prognosis in established diagnoses of melanoma was also evaluated. Methods: The Cancer Genomics Consortium Working Group for Melanocytic Lesions reviewed published data from January 1998 through September 2022 of CNAs in melanocytic lesions detected by either FISH or CMA and conducted a meta-analysis of the findings. Results: Specific abnormalities common in primary cutaneous melanomas of various subtypes and uveal melanomas were enumerated. Differences in CNAs found in primary versus metastatic lesions were also determined, and published evidence for prognosis was summarized. Conclusions: The working group established evidence-based recommendations for the use of CNA testing for evaluation of ambiguous melanocytic lesions. Full article

Glycogen synthase kinase-3 (GSK3) inhibition is a commonly used approach to promote osteogenic differentiation through activation of Wnt signaling. However, 6-bromoindirubin-3′-oxime (BIO), which is commonly used for GSK3 inhibition, also targets JAK/STAT, raising the possibility of dual pathway interference during osteoblast differentiation, as both GSK3 and JAK/STAT pathways are critical regulators of osteoblastogenesis. In this study, we investigated the effect of BIO on the osteoblast differentiation of hMSCs-TERT4. While BIO had no significant effect on cell viability or apoptosis, it markedly inhibited osteoblast differentiation, as evidenced by reduced ALP activity, decreased matrix mineralization, and downregulation of osteoblast-associated markers. Microarray analysis followed by qRT-PCR validation revealed downregulation of Wnt and TGF-β pathway genes. These findings show that BIO suppresses osteoblast commitment and osteogenic differentiation, accompanied by altered Wnt- and TGF-β-related gene expression. This study provides mechanistic insight into the off-target consequences of widely used small molecules and highlights the importance of dissecting pathway-specific roles in stem cell differentiation. Understanding the interplay between GSK3 and JAK signaling is essential for optimizing pharmacological strategies in skeletal regenerative medicine. This study highlights the importance of pathway selectivity when using small molecules in stem cell-based therapies for bone regeneration. Full article

Triple-negative breast cancer (TNBC) lacks effective targeted therapies, and the mechanisms by which developmental endothelial locus-1 (EDIL3/Del-1) promotes TNBC remain incompletely defined. We profiled Del-1 and AMPK subunits in TNBC cell lines by RT-PCR and immunoblotting, performed functional assays in CRISPR/Cas9 Del-1 knockout and AMPKβ-manipulated cells, and evaluated AMPKβ in early-stage TNBC tumors using tissue microarrays (TMA) (immunohistochemistry; n = 100) and AMPKβ2 mRNA quantification. Del-1 and AMPKβ were enriched in TNBC cells, most prominently in the mesenchymal stem-like subtype, whereas AMPKα levels were relatively stable. Increased Del-1 and activated AMPKβ enhanced proliferation and invasion, while Del-1 deletion reduced AMPKβ expression and suppressed tumor-promoting phenotypes. Mechanistically, Del-1 increased AMPKβ phosphorylation at serine 108, and a phospho-mimetic AMPKβ mutant further amplified oncogenic effects. In the pilot TMA study, high AMPKβ protein expression showed a trend toward poorer DFS in Kaplan–Meier analysis, while multivariate analysis identified high AMPKβ protein expression as an independent factor associated with poorer DFS in patients with early TNBC. These data support AMPKβ as a key mediator of Del-1-driven signaling and suggest AMPKβ could be a therapeutic target in aggressive TNBC subsets. Full article

Background/Objectives: This study assesses the genetic basis of fetal congenital heart disease (CHD), which exhibits a complex etiology, by using chromosomal microarray analysis (CMA); it also elucidates perinatal outcomes and postnatal development to support prenatal diagnosis and genetic counseling. Methods: Pregnant women (n = 1195) who were diagnosed with fetal CHD based on echocardiography were selected along with those having an interventional prenatal diagnosis, all of whom underwent CMA. Depending on the gestational age, amniotic fluid or umbilical cord blood samples were collected. Patients were included if they were diagnosed with fetal CHD based on echocardiography. Those who could not consent to amniocentesis or umbilical vein puncture or who had contraindications for amniocentesis or umbilical vein puncture were excluded. Patients were studied until May 2025. Results: Of the 1195 fetuses with CHD, 140 had pathogenic copy number variation (pCNV). The pCNV detection rate in cases with a single CHD was 3.17%, whereas it was 13.51% in the group with multiple CHDs. The detection rate for pCNVs in patients with extracardiac abnormalities was 28.62%. The fetal and postnatal mortality rates were highest for fetuses with multiple CHDs. The survival rate was highest for fetuses with a single CHD. Early detection of CHD and timely genetic testing can inform clinical management of CHD-affected pregnancies; however, larger prospective studies are needed to establish their impact on perinatal outcomes. Conclusions: CMA provides valuable information for genetic counselling, as it identifies pathogenic variants associated with CHD. However, prognostic predictions should consider multiple clinical factors. Full article

Following the establishment of the four molecular subtypes of breast cancer, additional biomarkers are required to further refine prognostication and patient stratification. Krüppel-like factors (KLFs), components of Wnt signaling, estrogen receptor beta (ERβ) isoforms, cyclin D1, and E-cadherin have been implicated in epithelial–mesenchymal transition, tumor proliferation, and disease progression. In this monocentric retrospective cohort study, tissue microarrays from 153 patients with histologically confirmed breast cancer were analyzed by immunohistochemistry to assess the expression of cytoplasmic Dkk1, β-catenin, and E-cadherin, as well as nuclear cyclin D1, KLF-4, KLF-5, and ERβ isoforms, using the Remmele and Stegner immunoreactive score. Associations between protein expression patterns with clinicopathological characteristics and survival outcomes using univariable and multivariable Cox regression analyses were examined. High cytoplasmic E-cadherin expression was associated with improved overall survival [hazard ratio (HR) 0.37, 95% confidence interval (95% CI) 0.18–0.77, p = 0.008], whereas high nuclear expression of KLF-4 (HR 2.63, 95% CI 1.32–5.22, p = 0.006) and KLF-5 (HR 2.16, 95% CI 1.01–4.65, p = 0.048) was associated with reduced overall survival. High ERβ1 expression showed a marginally protective association with the development of metastases (log-rank test p = 0.045). Importantly, nuclear KLF-4 expression remained independently associated with adverse overall survival after adjustment for tumor stage, lymph node status, molecular subtype, and other molecular markers (adjusted HR 4.09, 95% CI 1.93–8.67, p < 0.001). These findings identify nuclear KLF-4 as an adverse prognostic marker in breast cancer and support its potential relevance for molecular patient stratification. Full article

Endometriosis is a heterogeneous chronic inflammatory disorder associated with substantial diagnostic delay and limited therapeutic options, highlighting the need of robust non-invasive biomarkers and actionable molecular targets to complement existing low-sensitivity tests. To identify conserved pathogenic mechanisms with translational potential, here, we uniformly reprocessed three independent the Gene Expression Omnibus (GEO) microarray cohorts (GSE7305, GSE25628, and GSE11691) and applied a strict, directionally consistent intersection strategy to identify conserved transcriptional signals. We identified 262 consensus differentially expressed genes enriched for immunity/inflammation, cell adhesion and migration, and angiogenesis, consistent with key biological hallmarks of lesion establishment and persistence. Protein–protein interaction topology prioritized 11 highly connected hub genes (VCAM1, CCL2, MCAM, CD14, CD24, FGFR1, SIRPA, CSF1R, S100A9, S100A8, and LY96) that likely act as an integrated immune-adhesion-angiogenesis axis. Notably, 63/262 (24%) of the consensus genes were annotated to the extracellular exosome compartment, supporting their translational relevance as liquid-biopsy candidates. Finally, connectivity mapping using the LINCS L1000 framework nominated small-molecule perturbagens predicted to reverse the endometriosis-associated signature, providing a rational starting point for drug-repurposing experiments. In conclusion, this study elucidates a conserved immune–adhesion–angiogenesis axis driven by an 11-gene hub network in endometriosis. These core regulators represent promising candidates for the development of non-invasive liquid biopsies and precision, non-hormonal therapeutics. Full article

Background/Objectives: Umbilical–portal–systemic venous shunts (UPSVS) are rare fetal vascular anomalies with heterogeneous embryologic origins and variable perinatal implications. Although prenatal diagnosis has increased with advances in fetal imaging, data correlating prenatal subclassification with structural/genetic abnormalities and neonatal outcomes remain limited. Methods: This retrospective study included 50 fetuses prenatally diagnosed with UPSVS at a tertiary referral perinatology center between 2021 and 2025. Cases were subclassified according to the Achiron prenatal classification into Type 1 umbilical–systemic shunt (USS), Type 2 ductus venosus–systemic shunt (DVSS), Type 3a intrahepatic portosystemic shunt (IHPSS), and Type 3b extrahepatic portosystemic shunt (EHPSS). Prenatal ultrasound, Doppler, fetal echocardiography, and genetic testing (karyotype and chromosomal microarray) were analyzed. Perinatal metrics—including structural/genetic anomalies, fetal growth restriction (FGR), termination of pregnancy (TOP), and neonatal outcomes—were evaluated with postnatal verification. Results: The distribution of subtypes was Type 1: 28% (14/50), Type 2: 48% (24/50), Type 3a: 20% (10/50), and Type 3b: 4% (2/50). Gestational age at diagnosis was significantly higher in Type 3a compared with Type 1 and Type 2 (32.2 ± 2.4 vs. 21.1 ± 6.7 and 22.4 ± 5.8 weeks; p < 0.001). Structural anomalies were most frequent in Type 1 (13/14, 92.9%; p < 0.001), while FGR predominated in Type 3a (9/10, 90%; p = 0.006). Ductus venosus (DV) agenesis was universal in Type 1 (14/14) and Type 3b (2/2), absent in Type 2 (0/24), and present in 20% of Type 3a (2/10) (p < 0.001). Genetic abnormalities were detected in 57% of Type 1 (4/7) and 56% of Type 2 (9/16) fetuses, with trisomy 21 most prevalent in Type 2. TOP was highest in Type 1 (8/14, 57.1%; p < 0.001). Adverse neonatal outcomes occurred primarily in Type 1 and Type 3b (p < 0.001), whereas Type 2 demonstrated favorable neonatal outcomes. Conclusions: UPSVS subtype is strongly associated with structural/genetic anomalies, FGR, and neonatal outcomes, underscoring the importance of prenatal subclassification in prognostic assessment and counseling. Type 1 and Type 3b represent the highest—risk subgroups requiring delivery planning in tertiary centers, while Type 2 generally exhibits a benign perinatal course. The association between Type 3a and FGR highlights the need for detailed evaluation of the hepatic venous system in growth-restricted fetuses. However, interpretation of subgroup-specific associations should consider the relatively small sample size of Type 3b cases and the limited genetic testing performed in some Type 3a fetuses. Multicenter prospective studies are warranted to standardize diagnostic algorithms, optimize genetic testing strategies, and refine perinatal management. Full article

Vertical jump performance is known to be a moderately heritable trait. However, previous studies on sport genetics have largely relied on candidate-gene approaches, which do not adequately reflect the polygenic nature of explosive performance, particularly among elite badminton players. Therefore, the aim of the present study was to identify genetic variants associated with lower-limb explosive performance, assessed via vertical jump measures, among elite Turkish badminton players using a genome-wide association study (GWAS) approach. The present study included 90 elite male (n = 47) and female (n = 43) badminton players, and 557 non-athletic controls sourced from a public database. Performance-related traits were evaluated through countermovement jump (CMJ), squat jump (SJ), and their differential. Genome-wide genotyping was performed using DNA microarrays, and associations were examined using linear mixed models fixed for sex/gender, body mass index, and sport experience. Although no variants reached genome-wide significance (p < 1.00 × 10⁻⁷), 13 single-nucleotide polymorphisms (SNPs) exceeded the suggestive threshold (p < 1.00 × 10⁻⁵). CMJ-associated variants were rs4905767, rs2911702, rs10246591, and rs9842454; SJ-associated variants were rs55817650, rs62318127, rs115197840, rs78317172, and rs35930589; and CMJ–SJ-associated variants were rs34638064, rs6679342, rs4931233, and rs9442615. The present study provides preliminary evidence that lower-limb explosive performance among elite badminton players is polygenic, involving regulatory and signaling pathways rather than single performance genes. Full article

Background/Objective: Di-2-ethylhexyl phthalate and its bioactive metabolite mono-2-ethylhexyl phthalate (MEHP) are ubiquitous endocrine-disrupting chemicals implicated in carcinogenesis. However, the molecular mechanisms linking MEHP exposure, host genetic susceptibility, and prostate cancer progression remain incompletely defined. Methods: We integrated transcriptomic profiling of MEHP-exposed human prostate epithelial cells with a genetic association study of 630 patients with prostate cancer receiving androgen deprivation therapy. MEHP-responsive genes were identified from public microarray datasets and subjected to pathway enrichment analyses. Germline single-nucleotide polymorphisms (SNPs) in MEHP-regulated genes were evaluated for their association with progression-free survival, overall survival, and cancer-specific survival. The clinical and functional relevance of the key genes was further assessed using large-scale public prostate cancer expression datasets. Results: MEHP exposure induced widespread transcriptional reprogramming, prominently suppressing focal adhesion and cell–matrix interaction pathways. Genetic analyses identified multiple prognostically relevant SNPs within MEHP-responsive genes, with anoctamin 4 (ANO4) variants showing consistent associations across all clinical endpoints. The minor allele of rs17485225 in ANO4 was significantly associated with reduced all-cause and prostate cancer-specific mortality. Pooled analyses revealed reduced ANO4 expression levels in prostate cancer tissues and improved survival in patients with high ANO4 expression levels. Pathway analyses linked low ANO4 expression levels with enhanced cell cycle activity and compromised cell adhesion. Conclusions: Our findings suggest that ANO4 may act as a mediator of MEHP-associated prostate cancer progression and support a gene–environment interaction model in which environmental toxicant exposure and germline variation converge on focal adhesion dysregulation to potentially contribute to aggressive disease. Full article

Understanding the molecular mechanisms of carcinogenesis, including disruptions in the homologous recombination system, is fundamental to understanding malignant transformation. Dysfunction of homologous recombination genes, such as BRCA1 and BRCA2, contributes to genomic instability and the development of more aggressive tumor clones. The use of chemical carcinogens enables the modeling of tumor formation and the monitoring of changes in molecular genetic parameters. This approach is important for understanding how tumor cells adapt to genotoxic stress and for advancing the development of personalized cancer therapies. The objective of this study was to evaluate the expression of key homologous recombination system genes in a model of chemically induced carcinogenesis in mice. Materials and Methods: Male outbred ICR (CD-1) laboratory mice (n = 40) were used to study chemically induced carcinogenesis. The animals were divided into four groups: two control groups and two experimental groups, which received 3-methylcholanthrene (MC) or trichloroacetic acid (TCA). Tumor cells were identified by histological analysis of autopsy material using light microscopy after standard hematoxylin and eosin staining. RNA and DNA were extracted from cell suspensions using the RNeasy Plus Mini Kit and QIAamp DNA Mini Kit (Qiagen, Hilden, Germany), respectively. The expression levels of homologous recombination genes were assessed by RT-PCR and microarray analysis. Digital PCR was performed to assess chromosomal aberrations in the Brca1 gene. Results: Tumor formations were identified in laboratory animals two months after 3-methylcholanthrene. Histological analysis revealed morphological changes in a pleomorphic cell tumor, forming diverse, multidirectional fascicular and swirling structures, as well as large solid foci composed of markedly polymorphic spindle-shaped and epithelioid cells. Analysis of copy number aberrations in the examined samples showed that the frequency of Brca1 deletions was 60%, while 40% of animals had normal gene copy number. To further characterize the molecular changes, we assessed gene expression levels through expression microarray analysis. A total of 14 genes were hypoexpressed in the tumor compared to the normal tissue, with p < 0.05. A high level of differential expression was characteristic for Rad50, Rad51, Brca1, Brca2, and Pold4. Two genes, Rad52 and Bard1, exhibited increased expression levels. It was shown that as the tumor mass increased, so did the frequency of homologous recombination genes with hypoexpression. Conclusions: Our findings confirm that MC and TCA influence tumor formation and reveal that suppression of homologous recombination genes may contribute to this process. In addition, it has been established that as tumors progress, the expression of DNA repair genes declines and aberrant gene states accumulate. These data emphasize the importance of studying the state of DNA repair genes for the development of more effective strategies for cancer diagnosis and therapy. Full article

Background: Sirtuin 3 (SIRT3), a mitochondrial NAD⁺-dependent deacetylase, plays a central role in regulating mitochondrial metabolism, oxidative stress, and cell survival. Although SIRT3 has been implicated in angiogenesis, apoptosis, and inflammation, its global proteomic impact on the brain remains unclear. This study aimed to systematically characterize alterations in angiogenesis-, apoptosis-, chemokine-, and cytokine-related proteins in the brains of SIRT3 knockout (SIRT3 KO aka SIRT3⁻/⁻) mice compared with wild-type (WT) controls. Methods: Adult male C57BL/6 WT and SIRT3 KO mice were analyzed using proteome profiler antibody microarrays covering 53 angiogenesis factors, 21 apoptosis markers, 28 chemokines, and 111 cytokines. Protein expression changes were quantified by chemiluminescence imaging and densitometric analysis. Results: The results showed a distinct suppression of angiogenic proteins (amphiregulin, angiogenin, DPPIV, GM-CSF, IGFBP-2, IGFBP-3, IL-1β, PDGF-AA, PDGF-BB, proliferin, serpin F1, thrombospeondin-2, TIMP-4, and VEGF-B), activation of both pro-apoptotic (BAD, cytochrome c, Smac/DIABLO, HIF-1α, Fas, TNF R1, and TRAILR2) and anti-apoptotic, stress-related proteins (Bcl-x, catalase, HO/HMOX2, HSP27, HSP70, and MCL1) in the SIRT3 KO animals compared with the WT controls. Notably, SIRT3 deficiency was associated with increased expression of inflammatory mediators linked to glial activation and neurodegeneration (BLC/CCL13, LIX/CXCL5, MIG/CXCL9, chitinase 3-like 1, CCL22/MDC, IL-6, myeloperoxidase, osteopontin, RBP4, Reg3G, and TNF-α), alongside disturbed proteins involved in immune surveillance and vascular remodeling (6Ckine/CCL21, chemerin, DF, EGF, fractalkine/CX3CL1, HGF, IGFBP-6, IL-16, and I-TAC). Conclusions: Collectively, these findings demonstrate that SIRT3 is a key regulator of mitochondrial-dependent vascular, apoptotic, and neuroimmune pathways in the brain, and that its loss creates a molecular environment consistent with heightened vulnerability to neurodegenerative processes. Full article

The speckle-type BTB/POZ protein (SPOP) is an E3 ubiquitin ligase adaptor typically considered a tumor suppressor, yet its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study investigated SPOP expression, arecoline regulation, and its potential as a HNSCC biomarker. SPOP mRNA and its protein were quantified in HNSCC (FaDu, GMN, HSC-3, SAS, and A253) and normal oral epithelial (SG) cell lines via RT-qPCR and Western blot; arecoline’s effect on SG, SAS, and A253 cells was evaluated. SPOP mRNA was analyzed using The Cancer Genome Atlas (TCGA) HNSCC cohort, and protein localization was assessed via immunohistochemistry (IHC) on tissue microarrays. SPOP mRNA was higher in some HNSCC lines; arecoline induced SPOP in SG cells, but not in HNSCC cell lines. TCGA confirmed SPOP mRNA upregulation in tumors correlating with grade. IHC showed SPOP upregulation in HNSCC, particularly in palate and pharynx/hypopharynx sites. The nuclear SPOP-positive ratio shifted from 12.14 ± 9.82% in normal tissues to 61.26 ± 33.03% in tumors (p < 0.0001), differentiating grades and sites better than total expression. SPOP is upregulated in HNSCC and inducible by arecoline. Enhanced nuclear SPOP localization indicates malignancy and progression, identifying it as a potential HNSCC diagnostic and progression biomarker. Full article

Background/Objectives: We aimed to identify angiogenesis-related prognostic biomarkers and develop a radiogenomics model to predict overall survival (OS) in clear cell renal cell carcinoma (ccRCC), supporting risk stratification and potential therapeutic target discovery. Methods: Bulk transcriptomes from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma cohort (TCGA-KIRC), seven Gene Expression Omnibus (GEO) microarrays, and a single-cell RNA sequencing (scRNA-seq) dataset were integrated to identify angiogenesis-related prognostic genes. Preoperative contrast-enhanced computed tomography (CT) images from The Cancer Imaging Archive Kidney Renal Clear Cell Carcinoma collection (TCIA-KIRC) were used for radiomics feature extraction, and a radiogenomics signature was constructed by linking radiomic features with transcriptomic risk patterns. Nine machine learning models were trained to predict OS; the best model was further evaluated in an independent external retrospective cohort. PDLIM1 (PDZ and LIM domain protein 1) was validated at the protein level, and conditioned medium from stable ccRCC cell lines was applied to human umbilical vein endothelial cells (HUVECs) for Matrigel tube formation assays. Results: Five angiogenesis-related hub genes (PDLIM1, EMCN, ARPC1B, PLAT, and TIMP1) were identified. The extreme gradient boosting (XGBoost)-based radiogenomics model showed the best performance, with time-dependent concordance index (C-index) values of 0.880, 0.816, and 0.789 at 1, 3, and 5 years in the training set and 0.864, 0.758, and 0.736 in the internal validation set, respectively. In the external validation cohort, C-index values were 0.800, 0.726, and 0.703 at 1, 3, and 5 years. PDLIM1 protein was upregulated in ccRCC versus normal tissues. Functionally, PDLIM1 overexpression suppressed, whereas PDLIM1 knockdown promoted tube formation. Conclusions: This study developed and validated an angiogenesis-related radiogenomics model that accurately predicts OS in ccRCC patients and provides potential therapeutic targets for anti-angiogenic therapy. Full article