Search Results (437)

Background: Chronic nonbacterial prostatitis (CNP), the major subset of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), imposes a substantial global burden yet lacks satisfactory therapies. Maizibizi Wan (MZBZ) has long been used clinically for prostatitis, but its pharmacodynamic substance basis and mechanisms remain unclear. Methods: Ultra-high-performance liquid chromatography–Q-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS) coupled with Global Natural Products Social Molecular Networking (GNPS) molecular networking profiled MZBZ constituents and rat plasma–exposed prototype components and metabolites was used. Based on blood-absorbable components, network pharmacology predicted core targets/pathways; representative interactions were validated by molecular docking. A λ-carrageenan–induced CNBP rat model underwent histopathology (H&E), serum cytokine assays (TNF-α, IL-1β, IL-6/IL-17), immunohistochemistry (COX-2, TNF-α, MMP-9), and Western blotting (P-p65/p65, p-AKT/AKT, COX-2, TGF-β1, BCL2). Results: A total of 188 chemical constituents were identified in MZBZ (79 flavonoids, 38 organic acids, 30 alkaloids, 15 phenylpropanoids, 7 steroids, 4 phenylethanoid glycosides, 15 others). A total of 35 blood-absorbable components (18 prototype components, 17 metabolites) were identified, mainly involving Phase I oxidation and Phase II glucuronidation/sulfation. Network analysis yielded 54 core targets enriched in NF-κB and PI3K/AKT signaling and apoptosis. Docking indicated stable binding of key flavonoids to COX-2, NFKB1, TNF, IL-6, and BCL2. In vivo, MZBZ ameliorated prostatic inflammation, reduced serum TNF-α/IL-1β/IL-6/IL-17 (p < 0.05 or p < 0.01); decreased P-p65/p65, p-AKT/AKT, COX-2, and TGF-β1; and increased BCL2 in prostate tissue. Conclusions: MZBZ exerts anti-CNBP effects via multi-component synergy (prototypes + metabolites) that suppresses inflammatory cytokines, modulates apoptosis, and inhibits NF-κB and PI3K/AKT pathways. These findings provide a mechanistic basis and quality control cues for the rational clinical use of MZBZ. Full article

Background: Saffron (Crocus sativus L.) corms, often discarded as agricultural by-products, are a promising and sustainable source of bioactive metabolites with potential therapeutic relevance. However, their anticancer potential remains largely underinvestigated. Objectives: This study aimed to compare the phytochemical composition of hydroethanolic extracts from fresh (HEEF) and stored (HEES) saffron corms and to evaluate their anticancer effectiveness against colorectal cancer cells. Methods: Phytochemical profiling was performed using HPLC-ESI-QTOF-MS/MS. Cytotoxicity against T84 and SW480 colorectal cancer cell lines was determined by the crystal violet assay. Apoptosis-related protein modulation was assessed by Western blotting. Additionally, molecular docking, molecular dynamics simulations, and MM/GBSA calculations were used to investigate ligand–target binding affinities and stability. Results: Both extracts contained diverse primary and secondary metabolites, including phenolic acids, flavonoids, triterpenoids, lignans, anthraquinones, carotenoids, sugars, and fatty acids. HEES showed higher relative abundance of key bioactive metabolites than HEEF, which was enriched mainly in primary metabolites. HEES showed significantly greater dose-dependent cytotoxicity, particularly against SW480 cells after 24 h (IC₅₀ = 34.85 ± 3.35). Apoptosis induction was confirmed through increased expression of caspase-9 and p53 in T84 cells. In silico studies revealed strong and stable interactions of major metabolites, especially 3,8-dihydroxy-1-methylanthraquinone-2-carboxylic acid with COX2 and crocetin with VEGFR2. Conclusions: Stored saffron corms possess a richer bioactive profile and show enhanced anticancer effects in vitro compared with fresh saffron corms, suggesting that they may represent a promising source of compounds for the future development of colorectal cancer therapeutics. Full article

Ultraviolet B radiation is a major cause of skin aging, cellular senescence, and inflammaging, mediated by the excessive production of reactive oxygen species (ROS) and induction of apoptosis. This study evaluated the photo-protective effects of astaxanthin, one of the strongest natural antioxidants, in UVB-treated keratinocytes. The antioxidant capacity of astaxanthin was evaluated using ABTS, DPPH, and NBT/riboflavin/SOD assays. HaCaT cells were exposed to 30 mJ/cm² of UVB radiation. Photoprotective effects and accumulated ROS were evaluated in UVB-irradiated HaCaT cells by MTT and DCFH-DA assays. Nitric oxide levels were quantified using the Griess reagent. Apoptosis was assessed by dual staining using acridine orange/ethidium bromide, lysosomal integrity by acridine orange uptake, and cell migration by scratch assay. Cell adhesion was assessed on ECM-coated Nunc plates. Finally, we formulated a 0.5% astaxanthin-enriched cream. Astaxanthin mitigated UVB-induced damage by reducing intracellular ROS levels by 3.7-fold, decreasing nitric oxide production to 29.8 ± 7.7% at the highest concentration, and maintaining lysosomal integrity. The carotenoid significantly enhanced cell viability, increasing it from 60.64 ± 8.3% in UV-treated cells to 102.1 ± 3.22% at 40 µM. Moreover, treated cells showed a significant reduction (p < 0.001) in the apoptotic rate (37.7 ± 3.1 vs. 87.7 ± 3.8 in UVB-irradiated cells, as evidenced by reduced chromatin condensation and nuclear fragmentation. Astaxanthin also enhanced tissue repair, as evidenced by increased cell migration and adhesion to several extracellular matrix (ECM) proteins (poly-L-lysine, laminin, fibrinogen, vitronectin and collagen I). In silico molecular docking predicted strong binding affinities between astaxanthin and key cellular targets, including JAK2 (−9.9 kcal/mol, highest affinity), STAT3, FAK, COX-2, NF-k-B, MMP2, and MMP9. The formulated cream demonstrated an in vitro SPF of 7.2 ± 2.5. Astaxanthin acts as a multifunctional photoprotective compound, providing a strong rationale for its incorporation into cosmetic and dermatological formulations, as further supported by the successful formulation and in vitro SPF estimation of an astaxanthin-enriched cream. Full article

Objective: Advanced glycation end-products (AGEs) contribute to oxidative stress and inflammation, leading to various disorders, including skin inflammation. Here, we investigated the anti-inflammatory effects of Aloe vera flower (AVF) extract and its active constituents, vitexin (V) and isovitexin (IV), in a glyoxal-derived AGE (GO-AGE)-induced skin inflammaging model. Methods: We evaluated the effects of AVF, V, and IV in epidermal keratinocytes (HaCaT cells) using enzyme-linked immunosorbent assay, Western blotting, quantitative real-time polymerase chain reaction, and in silico molecular docking. Results: Treatment of HaCaT cells with AVF, V, or IV significantly suppressed the secretion and expression of interleukins (IL-6 and IL-8) at both the mRNA and protein level, and reduced the expression of key inflammatory proteins, including kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2), and phosphorylation of mitogen-activated protein kinase (MAPK) pathway proteins. Notably, the inhibitory effects of V and IV on COX-2 expression were more comparable to or exceeded those of the positive control (Epigallocatechin gallate), even at a lower concentration. Conversely, the expression of sirtuin 1 (SIRT1) was upregulated by AVF, V, and IV, with IV showing 1.5-fold upregulation. Molecular docking analyses supported these findings, with IV displaying a particularly high binding affinity for COX-2 (−11.0 kcal/mol). Conclusions: These findings highlight the potential of AVF, V, and IV as novel therapeutic agents for managing skin inflammaging by modulating inflammatory pathways. Full article

Chaenomeles speciosa (Sweet) Nakai (CF), a traditional food in East Asia and a recent addition to clinical dietary recommendations, has demonstrated potential for managing hyperuricemia. However, its bioactive components and therapeutic mechanisms remain largely unexplored. In this study, we used an integrative approach incorporating serum pharmacochemistry, metabolomics, bioinformatics, molecular docking, and in vitro/vivo validation to investigate CF’s effects and mechanisms in hyperuricemia. In hyperuricemic mice, CF significantly reduced serum uric acid, creatinine, and blood urea nitrogen (BUN) levels, improved kidney histopathology, and restored redox balance by increasing antioxidant enzyme activities (SOD and GSH-Px) while lowering malondialdehyde (MDA) levels. Metabolomic analysis revealed that CF modulated pathways associated with oxidative stress, including purine metabolism, arachidonic acid metabolism, and α-linolenic acid metabolism, to reverse hyperuricemia-associated metabolic perturbations. Correlation analysis between differential metabolites and serum-absorbed constituents identified androsin, cynaroside, and salicin as potential bioactive compounds. These compounds showed high predicted binding affinities to COX-1, PGE2, and XOD in molecular docking, and these interactions were validated by in vitro assays, where the compounds effectively suppressed inflammatory cytokine production and inhibited XOD activity. Overall, CF exerts anti-hyperuricemic and renoprotective effects through coordinated regulation of purine metabolism, inflammation, and oxidative stress, supporting its potential as a functional food or complementary therapy for hyperuricemia-related conditions. Full article

Aspartame, a widely used artificial sweetener, has been linked to various cancers, including kidney renal papillary cell carcinoma (KIRP). However, the molecular mechanisms underlying this association remain unclear. This study employed network toxicology and molecular docking to investigate potential mechanisms of aspartame-induced KIRP. Differentially expressed genes from TCGA were intersected with aspartame targets and KIRP-related genes, yielding 61 common targets. GO and KEGG analyses revealed enrichment in extracellular matrix degradation, signaling pathways, and immune microenvironment regulation. Univariate Cox regression identified 23 prognostically significant genes, from which multifactorial Cox regression with stepwise selection determined 8 core genes (APLNR, CYP2C19, EDNRA, KLK5, F2R, RAD51, AURKA, and TLR2). A risk model was constructed and validated through VIF analysis, Schoenfeld residual testing, and internal validation using a training–validation split. SHAP analysis identified EDNRA as the primary driver gene. Survival analysis demonstrated that the model effectively stratified KIRP patients, with risk score and tumor stage serving as independent prognostic factors. Molecular docking confirmed stable binding between aspartame and core target proteins. These findings provide mechanistic insights into aspartame-induced KIRP pathogenesis and establish a foundation for future experimental validation. Full article

Skin aging, driven by oxidative stress, UV exposure, inflammation, and extracellular matrix degradation, necessitates the discovery of safer, multi-target natural products. We established an integrated pipeline combining UHPLC–MS/MS metabolomics, computational methods (network pharmacology, molecular docking, and dynamics simulation), and in vitro bioassays to efficiently discover and mechanistically characterize anti-aging compounds from novel botanical sources. We applied this pipeline to identify and evaluate Tephroseris flammea, a previously unassessed plant. Metabolomic profiling identified 21 compounds, including flavonoids, phenylpropanoids, and pyrrolizidine alkaloids. These compounds were linked via network pharmacology to 226 skin-aging-related targets, primarily involving inflammation (via AKT1, RELA) and matrix degradation (via MAPK3). Molecular docking and 100 ns molecular dynamics simulations confirmed stable ligand-target interactions with favorable binding energies. Validating these in silico predictions, the T. flammea extract demonstrated significant antioxidant activity and effectively suppressed key inflammatory mediators (IL-6, TNF-α, COX-2) and MMP-1 levels in UVB-exposed fibroblasts, notably without significant cytotoxicity. Collectively, this study validates the utility of our pipeline to mechanistically characterize complex botanicals, revealing that T. flammea contains multifunctional compounds modulating critical inflammatory and matrix-regulatory cascades. This work validates our pipeline for identifying novel, mechanistically defined ingredients from complex botanical sources. Full article

The substantial interest in plant-based drugs or plant-derived phytocompounds drives researchers to conduct comprehensive investigations on their therapeutic properties. Mollugin, one of the major active constituents of Rubia cardifolia, has been well-studied for its pharmacological properties, demonstrating potent anti-inflammatory properties by suppressing the TAK-1-mediated activation of NF-κB/MAPK and enhancing the Nrf2/HO-1-mediated antioxidant response. It exhibits strong anticancer effects through ferroptosis via IGF2BP3/GPX4 pathways, induces mitochondrial apoptosis, and targets NF-κB, ERK, and PI3K/Akt/mTOR to suppress tumor progression. Mollugin also inhibits JAK2/STAT and PARP1 pathways, suppressing IL-1β expression via the modulation of ZFP91. Moreover, it regulates the MAPK/p38 pathway, promotes neuroprotection, and improves cognitive performance through GLP-1 receptor activation. Mollugin promotes osteogenesis by activating the BMP-2/Smad1/5/8 signaling pathway and downregulates MAPK, Akt, and GSK3β expression, leading to the inhibition of osteoclastogenesis. It overcomes multidrug resistance by downregulating MDR1/P-gp, CREB, NF-κB, and COX-2 through AMPK activation. Its antibacterial effect is mediated by strong binding to FUR, UDP, and IpxB proteins in Enterobacter xiangfangensis. Mollugin mitigates Klebsiella pneumoniae infection, suppresses adipogenesis without causing cytotoxicity, and protects endothelial cells via the BDNF/TrkB-Akt signaling pathway. Synthetic derivatives of mollugin, such as oxomollugin and azamollugin, have shown enhanced anticancer and anti-inflammatory effects by regulating EGFR, PKM2, TLR4/MyD88/IRAK/TRAF6, and NF-κB/IRF3 pathways with improved solubility and stability. Collectively, these findings emphasize the broad-spectrum activity of mollugin. This review provides a critical interpretation of the mechanistic pathways regulated by mollugin and its derivatives, emphasizing their pharmacological significance and exploring their potential for future translation as multitarget drug candidates. Full article

The aim of this study was to investigate the molecular interactions of heparin, diclofenac, and their supramolecular complexes with cyclooxygenase enzymes (COX-1 and COX-2) using computational docking techniques. Diclofenac is a widely used nonsteroidal anti-inflammatory drug (NSAID) that inhibits COX isoforms, whereas heparin is a polyanionic glycosaminoglycan with established anticoagulant and emerging anti-inflammatory properties. Supramolecular association between these agents may modulate their physicochemical behavior and target engagement. Molecular modeling, dual-drug docking, and molecular dynamics (MD) simulations were employed to characterize the interactions of heparin, diclofenac, and pre-formed heparin–diclofenac complexes with COX-1 and COX-2. Geometry optimization and lipophilicity (logP) estimates were obtained using HyperChem, while protein–ligand docking was performed in HEX using crystallographic COX structures from the Protein Data Bank. Docking poses were analyzed in Chimera, and selected complexes were refined through short MD simulations. Pre-formed heparin–diclofenac assemblies exhibited markedly enhanced docking scores toward both COX isoforms compared with single ligands. Binding orientation strongly influenced affinity: for COX-1, the heparin–diclofenac configuration yielded the most favorable interaction, whereas for COX-2 the diclofenac–heparin configuration was preferred. Both assemblies adopted binding modes distinct from free diclofenac, suggesting cooperative electrostatic and hydrophobic contacts at the enzyme surface. Supramolecular complexation also altered calculated logP values relative to the individual compounds. MD simulations supported the relative stability of the top-ranked complex–COX assemblies. These findings indicate that heparin–diclofenac assemblies may enhance and reorganize predicted COX interactions in a configuration-dependent manner and illustrate the utility of dual-drug docking for modeling potential synergistic effects. Such insights may inform the design of localized or topical formulations, potentially incorporating non-anticoagulant heparin derivatives, to achieve effective COX inhibition with reduced systemic exposure. However, the results rely on simplified heparin fragments, legacy docking tools, and short MD simulations, and should therefore be interpreted qualitatively. Experimental studies will be essential to confirm whether such supramolecular assemblies form under physiological conditions and whether they influence COX inhibition in vivo. Full article

Airborne particulate matter (PM) triggers oxidative stress and inflammation in pulmonary tissues, contributing to chronic respiratory diseases. This study evaluated the antioxidant and anti-inflammatory effects of a combined extract of Haematococcus pluvialis (H. pluvialis) and walnut shell (HW extract) and its protective efficacy against PM_2.5-induced pulmonary inflammation. Extracts mixed at different ratios (10:0–0:10, w/w) were tested using 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging, cell-based assays, HPLC quantification, molecular docking, and a PM_2.5-induced pulmonary inflammation mouse model. The optimized 6:4 mixture showed the strongest antioxidant activity (RC₅₀ = 0.61 ± 0.14 μg/mL) and significantly reduced nitric oxide (NO) and cyclooxygenase-2 (COX-2) expression without cytotoxicity. HPLC confirmed the presence of astaxanthin (1.714 μg/mg) and quercetin (0.722 μg/mg). Docking simulations indicated strong COX-2 binding affinities (−9.501 and −8.753 kcal/mol) through hydrogen bonding and hydrophobic interactions. In vivo, HW extract reduced leukocyte infiltration, serum IL-6 levels, and pulmonary expression of COX-2, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) while improving alveolar structure. These results suggest that HW extract exerts synergistic antioxidant and anti-inflammatory actions via dual-site COX-2 modulation, providing a promising natural therapeutic approach for mitigating PM_2.5-induced respiratory inflammation. Full article

Oxidative stress, UV exposure, inflammation, and extracellular matrix degradation collectively drive skin aging, underscoring the need for safe, multi-target therapeutic options. We developed and applied an integrated analytical pipeline combining UHPLC–MS/MS metabolomics, computational analyses (network pharmacology, molecular docking, and molecular dynamics simulation), and experimental bioassays to efficiently identify and characterize novel natural products with anti-aging potential. This workflow was applied to Melampyrum roseum Maxim., a previously unassessed hemiparasitic plant of the Orobanchaceae family, to elucidate its bioactive potential against skin aging. UHPLC–MS/MS profiling annotated 13 secondary metabolites, predominantly flavone aglycones, iridoid glycosides, and phenylpropanoid derivatives. Network pharmacology analysis linked these metabolites to 172 potential skin-aging-associated targets, mainly within inflammatory, ECM, and oxidative-stress pathways. Molecular docking and 100-ns molecular dynamics simulations confirmed stable ligand-target interactions with favorable binding energies, particularly with AKT1, EGFR, PTGS2 and XDH. Validating these predictions, the M. roseum extract demonstrated significant antioxidant activity and effectively suppressed key inflammatory mediators (IL-6, TNF-α, COX-2) and MMP-1 levels in UVB-exposed fibroblasts, notably without significant cytotoxicity. Collectively, these findings demonstrate that M. roseum harbors multifunctional metabolites that modulate key inflammatory and matrix-regulatory pathways, providing preliminary mechanistic evidence for its potential as a promising candidate for natural anti-aging applications. Full article

Chrysanthemum (Chrysanthemum morifolium Ramat.) has been recognized as both a food and medicinal substance in China since 2002 and possesses antioxidant, anti-inflammatory, antibacterial, and immunomodulatory activities. Previous studies suggest that Chrysanthemum may alleviate skin lesions resembling atopic dermatitis (AD); however, its underlying mechanisms remain unclear. In this study, we integrated network pharmacology and machine learning to systematically explore the potential mechanisms of Chrysanthemum in AD treatment. Four algorithms—Random Forest (RF), Lasso regression with cross-validation (LassoCV), Elastic Net (EN), and Extreme Gradient Boosting (XGB)—were compared, among which the XGB model achieved the best performance (accuracy = 0.9393). Further analysis identified 15 optimal features, two core targets (PTGS2 and MMP9), and one critical pathway (NF-κB signaling). To experimentally validate these findings, HaCaT keratinocytes were co-stimulated with TNF-α and IFN-γ to establish an in vitro inflammatory model, and co-treatment with three major flavonoids from Chrysanthemum—Acacetin, Diosmetin, and Chryseriol—significantly suppressed cytokine-induced COX-2 overexpression and reduced NF-κB p65 phosphorylation, confirming their inhibitory effects on NF-κB activation. These results were consistent with molecular docking and dynamics simulations, which demonstrated that these flavonoids, along with celecoxib, could stably bind to COX-2, thereby enhancing system stability and reducing residue fluctuations at the binding interface, revealing the molecular basis by which Chrysanthemum alleviates AD and supporting its modernization and therapeutic potential. Full article

To resolve the ambiguous causal relationship between sleep disturbances and neurodegenerative diseases such as Alzheimer’s disease (AD), we conducted a multi-stage genetic and multi-omics investigation. Our large-scale bidirectional Mendelian randomization analysis identified a robust, asymmetrical pattern of genetic association, providing strong genetic evidence suggesting that liability for neurocognitive decline and AD is associated with sleep disturbances, with substantially weaker evidence for the reverse direction. To identify the underlying molecular drivers, a multi-omics Summary-data-based MR (SMR) analysis prioritized high-confidence causal genes, including YWHAZ, NT5C2, COX6B1, and CDK10. The predictive power of this gene signature was confirmed using machine learning models (ROC-AUC > 0.8), while functional validation through bulk and single-cell transcriptomics uncovered profound, cell-type-specific dysregulation in the AD brain, most notably opposing expression patterns between neurons and glial cells (e.g., YWHAZ was upregulated in excitatory neurons but downregulated in glia). Functional enrichment and network analyses implicated two core pathways—nucleotide metabolism centered on NT5C2 and synaptic function involving YWHAZ—and our investigation culminated in the identification of a promising therapeutic interaction, with molecular docking validating high-affinity binding between Ecdysterone and COX6B1 (docking score = −5.73 kcal/mol). Collectively, our findings strengthen the evidence that sleep disruption as a likely consequence of neurodegenerative processes and prioritize a set of validated, cell-type-specific gene targets within critical pathways, offering promising new avenues for therapeutic development. Full article

Background: Retinoid-binding proteins (RBPs) regulate retinoid metabolism and signaling, but their roles across human cancers remain incompletely defined. Methods: We conducted a comprehensive analysis using bioinformatics tools and experimental validations, examining RBP expression profiles across cancer types based on data from The Cancer Genome Atlas (TCGA). We employed survival analysis using the Kaplan–Meier method and utilized single-cell RNA sequencing (scRNA-seq) to investigate the roles of RBP4 and RBP7 in the tumor microenvironment. Results: Our analysis revealed significant downregulation of RBPs in multiple cancers, with RBP4 and RBP7 showing notable expression variations linked to tumor stages and grades. Cox analysis identified RBP4 as a protective gene in kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), and mesothelioma (MESO), while RBP7 exhibited protective effects in breast cancer (BRCA) and uveal melanoma (UVM). Conclusions: This pan-cancer and single-cell integrative analysis highlights the complex roles of RBPs in cancer progression and their potential as prognostic biomarkers, particularly RBP4 and RBP7 in breast cancer. These findings warrant further investigation into the functional mechanisms of RBPs, which may provide valuable strategies for therapeutic interventions. Full article

Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent urological malignancy, accounting for approximately 1.6% of all cancer-related deaths in 2022. While endocrine-disrupting chemicals (EDCs) have been implicated as risk factors for ccRCC, the toxicological profiles and immune mechanisms underlying Bisphenol A (BPA) exposure in ccRCC progression remain inadequately understood. Materials and Methods: Protein–protein interaction (PPI) analysis and visualization were performed on overlapping genes between ccRCC and BPA exposure. This was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to elucidate potential underlying mechanisms. Subsequently, 108 distinct machine learning algorithm combinations were evaluated to identify the optimal predictive model. An integrated CoxBoost and Ridge regression model was constructed to develop a prognostic signature, the performance of which was rigorously validated across two independent external datasets. Finally, molecular docking analyses were employed to investigate interactions between key genes and BPA. Results: A total of 114 overlapping targets associated with both ccRCC and BPA were identified. GO and KEGG analyses revealed enrichment in cancer-related pathways, including pathways in cancer, endocrine resistance, PD-L1 expression and PD-1 checkpoint signaling, T-cell receptor signaling, endocrine function, and immune responses. Machine learning algorithm selection identified the combined CoxBoost-Ridge approach as the optimal predictive model (achieving a training set concordance index (C-index) of 0.77). This model identified eight key genes (CHRM3, GABBR1, CCR4, KCNN4, PRKCE, CYP2C9, HPGD, FASN), which were the top-ranked by coefficient magnitude in the prognostic model. The prognostic signature demonstrated robust predictive performance in two independent external validation cohorts (C-index = 0.74 in cBioPortal; C-index = 0.81 in E-MTAB-1980). Furthermore, molecular docking analyses predicted strong binding affinities between BPA and these key targets (Vina scores all <−6.5 kcal/mol), suggesting a potential mechanism through which BPA may modulate their activity to promote renal carcinogenesis. Collectively, These findings suggested potential molecular mechanisms that may underpin BPA-induced ccRCC progression, generating hypotheses for future experimental validation. Conclusions: These findings enhance our understanding of the molecular mechanisms by which BPA induces ccRCC and highlight potential targets for therapeutic intervention, particularly in endocrine and immune-related pathways. This underscores the need for collaborative efforts to mitigate the impact of environmental toxins like BPA on public health. Full article