Integrative multi-omics reveals NQO1-mediated airway epithelial injury as a key mechanism of bisphenol A-induced COPD.

Toxicological Effects of Propyl 4-Hydroxybenzoate on Gallstone Pathogenesis: An Integrated Mendelian Randomization, Network Toxicology, and Experimental Study.

Bisphenol A exacerbates dry eye disease via the CASP1/GSDMD-mediated pyroptotic axis: network toxicology, mendelian randomization, and experimental validation

Background Bisphenol A (BPA) is a pervasive environmental contaminant associated with various systemic toxicities. However, its specific mechanistic involvement in dry eye disease (DED) pathogenesis is not defined. This study aimed to evaluate the toxicological mechanisms of BPA in DED pathogenesis and identify the key molecular mediators driving ocular surface injury. Methods Toxicity profiles of BPA were predicted using the ProTox and ADMETlab platforms. Network toxicology and machine learning were used to explore pathogenic pathways and molecular mechanisms. Mendelian randomization (MR) analysis was performed to assess the causal effects of candidate targets on DED. Immune infiltration analysis and Gene Set Enrichment Analysis (GSEA) were used to characterize functional features and immune associations. Molecular docking and molecular dynamics (MD) simulations evaluated the spatial engagement and stability between BPA and the hub target. Finally, in vitro assays (CCK-8, LDH release, propidium iodide staining, ROS detection, qRT-PCR, and Western blot) using human corneal epithelial cells (HCECs) were conducted to validate the BPA-induced cytotoxicity and the molecular mechanisms. Results Toxicity assessments predicted significant ocular irritant and corrosive properties for BPA. Machine learning algorithms identified CASP1 as the hub gene. MR analysis provided genetic evidence that elevated CASP1 expression causally increases DED risk (OR = 1.11, 95% CI: 1.06–1.16). Molecular docking demonstrated stable binding affinity (−5.1 kcal/mol) between BPA and the CASP1 protein. 100-ns molecular dynamics simulations confirmed its structural equilibrium and spontaneous thermodynamic stability with an MM-PBSA binding free energy of −12.19 kcal/mol. In vitro, BPA exposure decreased HCEC viability, compromised membrane integrity, and triggered significant intracellular ROS accumulation. BPA significantly upregulated the mRNA and protein expression of caspase-1, GSDMD, IL-1β, and IL-18. The application of a CASP1 inhibitor reversed these alterations and mitigated ROS accumulation. Conclusion This study suggests that CASP1 is a central molecular component in DED. BPA promotes ocular surface injury by activating the CASP1/GSDMD-mediated pyroptotic axis and its associated inflammatory cascade. Inhibition of CASP1 effectively abrogates this process, suggesting potential avenues for clinical intervention.

Bisphenol A and F exposure suppresses MMP9 to drive nasal epithelial inflammation and senescence: a protective target for allergic rhinitis.

Allergic rhinitis (AR) is a prevalent inflammatory disorder of the upper airways, and exposure to environmental endocrine-disrupting chemicals such as bisphenol A (BPA) and bisphenol F (BPF) has been implicated in its pathogenesis, yet the underlying molecular mechanisms remain poorly understood. We integrated network toxicology, bioinformatics, and machine learning approaches to identify key target genes linking BPA/BPF exposure to AR, followed by molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) to evaluate binding affinities. In vitro experiments using human nasal epithelial cells (HNEpC) were conducted to validate the effects of BPA/BPF on cell viability, apoptosis, inflammatory cytokines, senescence-associated secretory phenotype (SASP), and the NF-κB signaling pathway, with further functional assessment via MMP9 overexpression. Four common genes (MAPT, MMP9, CHRM3, ESR2) were identified for BPA and three (MMP9, CHRM3, ESR2) for BPF. SPR confirmed direct binding of both bisphenols to MMP9 with KD values of 3.46 μM (BPA) and 9.47 μM (BPF). BPA/BPF treatment inhibited cell viability, suppressed MMP9, promoted apoptosis, upregulated IL-4, IL-6, IL-8, IL-13, CCL2, TNF-α, and IL-1β, downregulated MMP1, and suppressed the NF-κB pathway. MMP9 overexpression reversed these effects. Our findings demonstrate that BPA and BPF promote AR pathogenesis through MMP9 suppression, SASP activation, and NF-κB inhibition, identifying MMP9 as a potential therapeutic target for pollutant-exacerbated AR.

Association between serum perfluoroalkyl substances and COPD risk: population evidence and in vitro validation.

Mixture exposure showed a significant positive association with chronic obstructive pulmonary disease risk, and these substances disrupt pulmonary homeostasis through concurrent molecular activation and lipid-metabolic disturbance, evidenced by triglyceride-glucose index mediation.

Integrated network pharmacology, transcriptomics and proteomics unveils the mechanisms of Forsythiae Fructus against acute lung injury

Association between TBPH exposure, increased MMP9 expression, and atherosclerosis: evidence from integrated network analysis and in vivo experiments

Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is used as a nonreactive brominated flame retardant used in industrial products, particularly in flexible polyvinyl chloride and rigid and flexible polyurethane foams. Although TBPH exposure poses potential health risks, its association with atherosclerosis remains poorly understood. This study integrated network toxicology, machine learning, molecular docking, and molecular dynamics (MD) simulations to elucidate the influence of TBPH on high-fat diet–induced atherosclerosis. TBPH exhibited significant predicted toxicity across multiple organs. In total, 167 potential TBPH targets and 690 atherosclerosis-associated targets were identified, with 108 overlapping targets obtained through intersectional analysis. A PPI network was constructed based on these 108 overlapping genes, and the top 20 hub genes were identified. In a parallel independent analysis using a public transcriptomic dataset, 111 differentially expressed genes (DEGs) were identified by comparing atherosclerotic and normal tissues. Subsequent intersection analysis of the 108 overlapping targets and 111 DEGs identified candidate genes that were both TBPH-related and differentially expressed in atherosclerosis. Public transcriptomic data showed higher matrix metalloproteinase 9 (MMP9) level in atherosclerotic tissues. The corresponding receiver operating characteristic (ROC) curve yielded an AUC of 0.806 (95% confidence interval [CI]: 0.698–0.914). Molecular docking and MD simulations indicated favorable predicted binding modes and computational stability between TBPH and MMP9. In vivo experiments further demonstrated an association between TBPH exposure, increased MMP9 expression, and high–fat diet–induced atherosclerotic lesions. These findings suggest that TBPH may be associated with high-fat diet–induced atherosclerosis progression through the dysregulation of key mediators, providing insight into environmental pollutant–driven disease development.