As one of the most widely used antibiotics in human and veterinary medicine, fluoroquinolones (FQs) have been recognized as environmental contaminants. They promote the dissemination of resistant strains and cause the imbalance in microbial community structures, threatening ecosystem stability and public health. Biodegradation is a promising sustainable approach for FQs removal. Many publications have described their environmental distribution, biodegradation mechanisms, and potential applications under aerobic and anaerobic conditions. Few reviews have comprehensively integrated recent progress. This review summarizes current research on FQs biodegradation, focusing on microbial degraders, biodegradation mechanisms, and critical influencing factors. Furthermore, we evaluate existing FQs removal technologies and propose ideas to address challenges in the practical application of FQs biodegradation. Overall, FQs biodegradation is primarily mediated by multiple enzyme systems especially CYP450, and is driven by representative degraders including Pseudomonas, Trametes versicolor, and Chlorella vulgaris. Integration with advanced treatment processes can markedly improve performance, achieving up to 94

Perfluorooctane sulfonate (PFOS), a persistent environmental pollutant, has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), yet the underlying molecular mechanisms remain incompletely characterized. We constructed an integrated analytical framework combining population epidemiology, network toxicology, machine learning, transcriptomic analysis, single-cell mapping, molecular docking, and experimental validation. NHANES data (n = 1,834) were analyzed to assess the association between serum PFOS concentrations and FLI-defined MASLD. Machine-learning analyses using LASSO and SVM-RFE prioritized candidate genes from 874 overlapping PFOS-MASLD-associated genes. Single-cell RNA sequencing resolved cell-type-specific expression patterns, while molecular docking evaluated potential PFOS-protein interactions. A 12-week murine exposure model provided in vivo validation. Epidemiological analysis identified a nonlinear association between serum PFOS and MASLD odds (p < 0.001), with effects evident at background exposure levels (7.76 ng/mL). Convergent machine-learning analyses prioritized five candidate genes: CYP7A1, GRIA3, PHLDA1, SOCS2, and WNT5A. An exploratory five-gene model yielded an apparent AUC of 0.998 (95

Decabromodiphenyl ethane (DBDPE), a novel brominated flame retardant, poses a recognized neurotoxic hazard, yet its mechanistic underpinnings in mammals remain largely undefined. This study aimed to elucidate the molecular mechanisms of DBDPE-induced neurotoxicity, and identify potential mitigation strategies. Subchronic oral exposure to DBDPE significantly increased hippocampal malondialdehyde (MDA), downregulated key neurotrophic and tight junction proteins, and elicited anxiety-like behavior alongside impairment in learning and memory ability. Mechanistically, DBDPE activated PERK-mediated endoplasmic reticulum stress (ERS), disrupted the structure and function of mitochondria-associated endoplasmic reticulum membranes (MAMs), as evidenced by downregulation of PACS2 and Mfn2. This disruption aberrantly activated the IP3R-GRP75-VDAC1 signaling pathway, promoting excessive Ca²⁺ transfer from the ER to mitochondria. The resultant mitochondrial Ca²⁺ overload triggered NCOA4-mediated ferritinophagy, exacerbating neuronal ferroptosis through Fe²⁺ accumulation and GPX4 depletion. Molecular docking experiments further revealed that DBDPE interacted with the low-affinity Ca²⁺-binding site of IP3R, maintaining it in a constitutively open state. Crucially, the IP3R inhibitor 2-APB significantly attenuated DBDPE-induced MAM dysfunction, mitochondrial damage, and ferroptosis in HT22 cells, supporting the critical contribution of IP3R to this toxicological process. In conclusion, our findings delineate a novel mechanistic pathway linking DBDPE exposure to neuronal ferroptosis via MAM disruption and Ca²⁺ dysregulation, and nominate IP3R as a potential therapeutic target for intervention.

Impaired wound healing and pathological scarring remain major clinical challenges, with immune cell dysregulation being a key driver of disease progression. Conventional in vitro models fail to recapitulate human immune responses, limiting their translational relevance. In recent years, advances in tissue engineering and microfluidic technologies have driven growing efforts to incorporate immune cells into in vitro models, thereby improving their ability to mimic pathological microenvironments. Among these, organ-on-a-chip technology stands out for its capacity to replicate dynamic perfusion, mechanical stimulation, and multicellular crosstalk-features critical for modeling immune-mediated wound repair. This review systematically summarizes recent progress in immune cell-integrated models of aberrant wound healing, including two-dimensional co-cultures, three-dimensional static cultures, organoid systems, and organ-on-a-chip platforms. We highlight core strategies for immune cell integration and their roles in recapitulating key pathological processes such as inflammation and fibrosis. Despite ongoing challenges in cell source stability, model standardization, and long-term culture viability, emerging strategies (e.g., organ-on-a-chip combined with three-dimensional bioprinting or modular design) offer new opportunities for creating biomimetic, high-throughput platforms for wound research. This review aims to facilitate the adoption of immune-integrated in vitro models in wound healing research, deepen mechanistic understanding of immune-driven pathology, and accelerate the development of precision therapeutics.

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of metabolic liver disease with high clinical relevance, but the lack of physiologically relevant human in vitro models has limited mechanistic studies and therapeutic development. Angelica sinensis polysaccharide (ASP) has shown promising efficacy in preclinical studies. This study aimed to establish a human liver organoid-based MASH model and apply it to investigate ASP as a representative intervention, given its hepatoprotective and metabolic regulatory properties. Methods: Human induced pluripotent stem cells (hiPSCs) were differentiated into liver organoids, and oleic acid was used to induce MASH-like phenotypes. ASP was selected to assess the model's responsiveness to metabolic interventions and was also tested in high-fat diet (HFD)-fed mice. Proteomic analyses were conducted to explore potential molecular targets and pathways. Results: hiPSCs-derived liver organoids formed 3D hollow multicell spheres containing parenchymal and nonparenchymal cells, exhibiting stable hepatic synthetic and metabolic functions. The model successfully recapitulates hallmark MASH features, including disrupted glucose and lipid metabolism as well as inflammatory and immune dysregulation. Leveraging the MASH-like organoid model, we found that ASP intervention alleviated hepatocellular injury and improved glucose and lipid homeostasis, consistent with findings in HFD-fed mouse models. Mechanistically, ASP might exert hepatoprotective effects by indirectly suppressing perilipin 2 (PLIN2) through insulin signaling, thereby linking glucose and lipid metabolism. Conclusion: A human-derived MASH-like organoid model was established as a physiologically relevant platform for mechanistic research and drug screening. The findings highlight the therapeutic potential of ASP and underscore the translational value of organoid-based disease models.

Succinate dehydrogenase (SDH) gene variants are the most common cause of the neuroendocrine tumour hereditary paraganglioma, which is associated with an over 20% metastasis risk as well as significant morbidity. There are currently no relevant human tumour cell lines or mouse models, and molecular understanding of downstream tumourigenic pathways is still rudimentary despite over two decades of concerted effort worldwide. These tumours generally show extremely slow in vivo doubling times (4-12 years), presumably existing in a primarily semi-quiescent state with little cell cycling or DNA replication. This characteristic makes deriving a useful tumour cell line impractical. A better alternative would be a cell line in which cell proliferation can be turned on and off at will, allowing expansion to generate sufficient cell numbers and experimentation once tumour cells have returned to their natural semi-quiescent state. The closest models currently available, highly-proliferating rat and mouse adrenal paraganglioma cell lines, are molecularly unrelated to SDH tumours. In this pilot study, we investigated whether primary SDH-derived paraganglioma tumour cells can be made to proliferate in vitro. We successfully transduced primary paraganglioma tumour cells with a lentiviral construct, using the proven strategy of c-MYC¬T58A (c-MYC) controlled by a Tet-On doxycycline-inducible expression system. We present the first evidence that primary paraganglioma chromaffin cells can be induced to proliferate in vitro, even in later passage cultures. Without any prior selection for chromaffin tumour cells, passaged cultures were obtained with over 80% synaptophysin-expressing chromaffin tumour cells, suggesting that this highly promising strategy deserves further exploration.

Perfluorooctanesulfonate (PFOS), a pervasive environmental pollutant, threatens respiratory health, though its pulmonary toxicity mechanisms remain unclear. The study integrated NHANES epidemiological data (n = 1595), computational toxicology (ADMETlab 3.0 and ProTox-3.0), chronic mouse exposure models (0, 5, and 150 μg kg-1 day-1, 12 weeks), multidatabase bioinformatics (CTD and GeneCards), PPI network analysis, and molecular docking (CB-DOCK2). NHANES analysis revealed a significant inverse correlation between serum PFOS and the FEV1/FVC ratio, indicating PFOS-associated airflow obstruction. Crucially, restricted cubic spline regression identified a unified toxicity threshold at 6.54 ng/mL, beyond which FEV1/FVC declined disproportionately. Computational prediction indicated >80% probability of PFOS respiratory toxicity. Animal experiments demonstrated dose-dependent injury: low dose primarily induced fibrosis, while high dose triggered apoptosis (TUNEL+/cleaved-caspase3). Bioinformatics integration identified metabolic dysregulation as the core mechanism, with KEGG enrichment highlighting glycolysis and xenobiotic metabolism. Core target validation showed PFOS bound with high affinity to AOX1 (-9.2 kcal/mol), GPI (-9.3 kcal/mol), PKM (-8.8 kcal/mol), and CYP1A1 (-9.0 kcal/mol) and suppressed Aox1 (P < 0.01) and Gpi/Pkm mRNA (P < 0.05). Additionally, PFOS exposure was accompanied by a decrease in GSH levels and an increase in MDA concentration, thereby inducing oxidative stress. PFOS drives pulmonary injury through dual metabolic hijacking: (1) disruption of AOX1-mediated oxidative defense leading to oxidative stress and (2) suppression of the GLUT1-GPI-PKM glycolytic axis. This study establishes AOX1 enzyme activity and the serum lactate/ATP ratio as promising noninvasive biomarkers for the early detection of PFOS-induced lung damage, offering significant insights for environmental health risk assessment.

As concern over tire-derived environmental contaminants continues to grow, the antioxidant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its oxidative transformation product, 6PPD-quinone (6PPDQ), have attracted increasing attention for their hepatotoxic potential. Despite accumulating evidence of 6PPDQ-induced liver injury, the molecular mechanisms linking this contaminant to non-alcoholic steatohepatitis (NASH) remain undefined. In this study, an integrated framework combining network toxicology, machine learning, and multi-omics analysis was employed to investigate the association between 6PPDQ exposure and NASH. Intersection of 1451 predicted 6PPDQ targets with NASH-related transcriptomic signatures yielded 52 overlapping candidate mediators enriched in oxidative stress, metabolic regulation, and inflammatory signaling pathways including ErbB, Notch, Hedgehog, Hippo, and TNF. Machine learning analysis across six algorithms identified five hub genes, EPHX2, ESD, FAS, SSB, and ZNF436, with individual AUC values ranging from 0.711 to 0.825. ESD was prioritized for focused analysis, and functional network analysis, eQTL-GWAS colocalization, immune infiltration profiling, single-cell RNA sequencing, and molecular docking together placed ESD within the lipid metabolic, apoptotic, and immunoregulatory circuits central to NASH pathogenesis. In vivo, male BALB/c mice (n = 6 per group) exposed intraperitoneally to 0.4 or 4 mg/kg 6PPDQ for 28 days developed histological liver injury, hepatic lipid accumulation, and α-SMA-positive profibrotic activation, accompanied by significantly increased hepatic inflammatory and profibrotic gene expression. Serum ALT and AST rose dose-dependently, and hepatic Esd was upregulated at both the mRNA and protein levels. These findings support a proposed ESD-centered adverse outcome pathway framework linking 6PPDQ exposure to NASH-related hepatic injury.

With the rapid expansion of tire production, the antioxidant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its transformation product, 6PPD-quinone (6PPDQ), have emerged as widespread environmental contaminants with demonstrated toxicity. Here, we employed an integrated network toxicology and computational framework to elucidate the mechanisms by which 6PPDQ may contribute to hepatocellular carcinoma (HCC). Transcriptomic data from four GEO datasets were normalized and analyzed using differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA), identifying 923 HCC-associated genes. Intersection with 3844 predicted 6PPDQ targets resulted in 148 candidate mediators. GO and KEGG analyses revealed enrichment in xenobiotic metabolism, redox regulation, and oncogenic pathways (e.g., PI3K-Akt, TNF, p53). Subsequent machine learning analysis identified nine hub genes, among which CHST4, SLC26A6, LY6E, and FAM13A formed a robust diagnostic signature (AUC = 0.999; Hosmer-Lemeshow P = 1.0). Single-sample gene set enrichment analysis (ssGSEA) and single-cell RNA sequencing (scRNA-seq) confirmed their cell type-specific expression and associations with altered immune infiltration. Molecular docking and 100 ns dynamics simulations demonstrated stable high-affinity binding between 6PPDQ and CHST4 (ΔG = -9.1 kcal/mol). Finally, we constructed an adverse outcome pathway (AOP) linking 6PPDQ exposure to immune dysregulation and HCC initiation. This multi-omics and in silico study reveals a mechanistic network by which 6PPDQ promotes hepatic carcinogenesis, highlights four candidate biomarkers for early detection, and provides a conceptual AOP framework for future toxicological and therapeutic investigations.

Microcystins (MCs), a group of potent hepatotoxins from cyanobacterial blooms, threaten global water security due to the resistance to conventional treatment processes and multi-organ toxicity to human. This study innovatively proposed a novel sequential process combining UV irradiation with biodegradation by Sphingopyxis sp. m6 for efficient microcystin-LR (MC-LR) removal. Results revealed that sequential UV-C pretreatment followed by Sphingopyxis sp. m6 biodegradation achieved complete degradation of 1 mg/L of MC-LR within 1 h of the biological phase, drastically reducing the treatment time compared to biodegradation alone (5 h). Mechanistic investigation revealed that low-dose UV-C (50 mJ/cm2) pretreatment induced MC-LR photoisomerization consistently with previously reported Adda geometric isomers. These photoisomers, along with residual parent MC-LR, were subsequently mineralized by Sphingopyxis sp. m6. Enzymatic pathway analysis confirmed a dual-pathway degradation, where Mlr enzymes processed both the native toxin and its isomeric forms, leading to a series of linearized peptides and Adda-derived products. Critically, the process achieved efficient detoxification, as confirmed by the restoration of HepG2 cell proliferation and protein phosphatase 2A activity. Moreover, response surface methodology optimized the key parameters (31.49 °C, pH of 7.36, 0.23 mg/L) for the highest degradation efficiency. This work provides an energy- and cost-efficient strategy for MC-LR remediation and elucidates the molecular mechanism of UV-induced photoisomerization facilitating subsequent biodegradation.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a widely used organophosphate flame retardant that is ubiquitously detected in environmental matrices and human biological samples, raising concerns about its potential health risks. However, the mechanisms underlying TDCPP-induced hepatotoxicity remain incompletely understood. Here, we investigated the hepatic effects of TDCPP using an integrated in vivo-in vitro approach combining a mouse exposure model, human-derived 3D liver organoids, and network toxicology analysis. Sub-chronic oral exposure to TDCPP in mice induced evident liver injury, characterized by histopathological alterations, elevated serum aminotransferase activities, and hepatic triglyceride accumulation accompanied by systemic lipid metabolism disorders. TDCPP exposure also disrupted hepatic redox homeostasis, as evidenced by glutathione depletion, enhanced lipid peroxidation, and downregulation of glutathione peroxidase 4, a key suppressor of ferroptosis. Consistently, TDCPP exposure reduced cell viability, promoted lipid droplet accumulation, increased reactive oxygen species levels, and suppressed GPX4 expression in human 3D liver organoids, recapitulating the major pathological features observed in vivo. Network toxicology analysis identified peroxisome proliferator-activated receptor gamma (PPARG) as a central node potentially involved in TDCPP-induced hepatotoxicity and ferroptosis, which was further supported by molecular docking analysis. Experimental validation confirmed that TDCPP exposure significantly upregulated PPARG expression in both mouse liver tissues and liver organoids. Overall, these findings indicate that TDCPP induces hepatic injury and lipid metabolic disturbance in association with ferroptosis, potentially mediated through a PPARG-GPX4 regulatory axis, providing human-relevant mechanistic insight into the hepatotoxic risk of this environmental contaminant.

Benzene exposure induces hematotoxicity, partially through disrupted DNA damage repair. SIRT6 is a key regulator of both DNA repair and metabolism. While its connection to metabolic reprogramming and novel lactylation modifications in benzene toxicity remains unknown. Herein, we found decreased SIRT6 expression in the peripheral WBCs of benzene-exposed workers. Furthermore, mediation analysis identified SIRT6, p16, and serum γ-H2AX levels as mediators of the inverse relationship between urinary S-PMA and WBC counts. In vitro, benzoquinone (BQ) suppressed SIRT6, enhanced glycolysis and lactate production, and induced DNA double-strand breaks (DSBs) and senescence. SIRT6-knockdown models confirmed that SIRT6 deficiency exacerbates benzene-induced increase in glycolysis and lactate accumulation. Crucially, lactate reduction with DCA attenuated DSBs and cellular senescence in bone marrow cells, mitigating hematopoietic damage. Mechanistically, we identified PRMT5 as a novel lactylation target of SIRT6 at lysine 240 (K240), a process that SIRT6 regulated through the lactyltransferase TIP60 and delactylase HDAC1. Functional studies in K240-mutant cells demonstrated that blocking lactylation at this site alleviated BQ-induced DSBs and senescence. Our findings establish that SIRT6 deficiency drives a lactate-fuelled lactylation of PRMT5 at K240, impairing DNA repair and promoting hematopoietic stem cell senescence caused by benzene. This work elucidates a previously unrecognized metabolic-epigenetic axis in benzene toxicity and highlights the therapeutic potential of targeting glycolytic flux or specific lactylation events to combat chemical-induced hematological damage.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a prevalent environmental pollutant, has been associated with an increased risk of Parkinson's disease (PD), yet the underlying molecular mechanisms remain poorly understood. To systematically elucidate these mechanisms, we employed an integrated computational and experimental approach. Network toxicology and molecular docking initially identified endothelial PAS domain protein 1 (EPAS1) as a high-priority target of TDCPP, exhibiting the strongest predicted binding affinity (-8.3 kcal/mol). This prediction was rigorously validated through in vivo experiments. Subchronic exposure of C57BL/6J mice to TDCPP (0, 0.03 0.3, 3, 30, and 300 mg/kg/day for 30 days) induced dose-dependent motor deficits, including reduced locomotor activity, impaired coordination in the pole test, and anxiety-like behavior. Pathological analysis revealed a substantial loss of tyrosine hydroxylase-positive (TH+) dopaminergic neurons in the substantia nigra (nearly 50% in the high-dose group) and a significant decrease in TH protein levels. Crucially, TDCPP exposure consistently upregulated EPAS1 protein expression in the midbrain. Finally, 100-ns molecular dynamics simulations confirmed the stability of the TDCPP-EPAS1 complex, demonstrating a rigid binding pocket and identifying Cys339 as a key interacting residue (96% contact fraction). Our study demonstrates that TDCPP promotes PD-like motor dysfunction and dopaminergic neurodegeneration, likely through a mechanism involving the direct targeting and upregulation of EPAS1 within the neurovascular unit. These findings provide novel, multi-layered evidence linking this common environmental contaminant to PD pathogenesis.

Background: Perfluorooctane sulfonic acid (PFOS) is a persistent environmental pollutant that accumulates in the liver, yet its metabolic effects under lipid overload remain unclear. Methods: We combined High Fat Diet (HFD)-fed mice, lipid-overloaded human liver organoids, machine learning based on human transcriptomic datasets, molecular modeling, and surface plasmon resonance (SPR) to investigate PFOS-induced disruption of hepatic glycogen–lipid homeostasis. Findings: PFOS alone caused modest metabolic alterations, whereas PFOS combined with lipid overload synergistically reduced glycogen storage and increased triglyceride (TG) and lipid droplet (LD) accumulation in mice and human liver organoids, exacerbating hepatic steatosis. Machine-learning analysis identified protein phosphatase 1 regulatory subunit 3G (PPP1R3G), a regulator of hepatic glycogen metabolism, as a candidate target. Molecular modeling and SPR supported direct PFOS–PPP1R3G binding. Under lipid overload, PFOS impaired PPP1R3G-associated glycogen synthesis and increased TG accumulation. PPP1R3G overexpression attenuated perilipin 2 (PLIN2) induction, supporting a model in which PPP1R3G dysfunction impairs glycogen synthesis and favors TG accumulation, while PLIN2 upregulation may stabilize TG-rich LDs and sustain intracellular lipid retention. Galangin restored PPP1R3G expression and ameliorated these metabolic disturbances in human liver organoids. Interpretation: PPP1R3G links PFOS exposure to disrupted glycogen–lipid homeostasis under lipid overload and represents a potential intervention target for environmentally aggravated hepatic steatosis.

BACKGROUND:Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a widely used organophosphorus flame retardant that has raised growing concern because it is persistent, can bioaccumulate, and is toxic. However, its possible role in chronic kidney disease (CKD) is still not well understood. METHODS:We used network toxicology, molecular docking, transcriptomic validation, and mouse exposure experiments to uncover the mechanisms linking TDCPP exposure to kidney injury. RESULTS:We found 1270 overlapping targets between predicted TDCPP-binding proteins and CKD-related genes. Enrichment analyses showed strong links to inflammatory and apoptotic processes, as well as key signaling pathways including PI3K-Akt, MAPK, Ras, and cAMP. Machine learning methods (LASSO, SVM-RFE, RF) identified two hub genes, CTRB1 and HSPA1A, which were both significantly downregulated in CKD transcriptomes and showed perfect diagnostic performance (AUC = 1.0). Immune cell analysis showed that CKD tissues had increased regulatory T cells, monocytes, M2 macrophages, and neutrophils, and CTRB1/HSPA1A expression was correlated with specific immune cell subsets. Molecular docking predicted favorable binding of TDCPP to both proteins, with the strongest affinity for CTRB1 (-7.2 kcal/mol). In vivo, TDCPP exposure caused dose-dependent tubular degeneration, inflammation, and increased serum BUN and creatinine, along with marked downregulation of CTRB1 and HSPA1A. CONCLUSION:Taken together, these findings suggest that TDCPP may contribute to CKD by disrupting CTRB1/HSPA1A and activating PI3K-Akt/MAPK signaling, which leads to immune dysregulation and progressive kidney injury. We propose a new adverse outcome pathway (AOP) framework linking TDCPP exposure to CKD, and highlight CTRB1 and HSPA1A as potential biomarkers and mechanistic targets for environmental nephrotoxicity.

Per- and polyfluoroalkyl substances (PFAS), particularly perfluorooctane sulfonate (PFOS), persist in humans and have been associated with cardiovascular outcomes, but cardiac-specific molecular responses remain incompletely characterized. We integrated transcriptomic screening, ensemble machine learning, molecular docking and 100-ns molecular dynamics, cross-species cardiac single-cell atlases with virtual knockout, and a time-stratified mouse exposure study (approximately 5 μg/kg/d for 4-8 weeks) to prioritize candidate molecular nodes associated with PFOS-related cardiac remodeling. Robustness analyses supported the stability of the machine-learning prioritization, and MYH6 was repeatedly selected and enriched in cardiomyocytes across human and mouse atlases. Docking and simulation supported a structurally plausible modeled PFOS-MYH6 complex. In exposed mice, Myh6 expression declined over time as septal asymmetry and interstitial fibrosis increased. Batch docking revealed 11 of 26 PFAS with scores at least as favorable as PFOS, indicating compound-level variation in modeled MYH6 compatibility. Together, the data prioritize MYH6 as a candidate molecular node associated with PFOS-related HCM-like remodeling and integrate these multiscale observations into a testable putative AOP-like hypothesis.

The rapid and accurate prediction of anticancer drug responses is critical for enhancing treatment efficacy and improving clinical outcomes in cancer patients. However, the practical implementation of current predictive models is hampered by dual limitations: machine learning approaches reliant on cell line data often exhibit suboptimal accuracy, while patient-derived organoids (PDOs) platform typically lack the rapid turnaround required for timely clinical decision-making. Here, we present a deep learning framework to predict drug response in lung cancer patients by integrating patient genomic sequencing data with compound structural information, trained against phenotypic drug sensitivity profiles from lung cancer PDOs, to predict drug responses in lung cancer patients. Our model enables individualized prediction of antitumor activity across diverse chemical structures, demonstrating capabilities for predicting efficacy of both approved drugs and novel compounds, as well as facilitating drug repurposing. The framework achieved 81.6% prediction accuracy, which was experimentally validated using patient-derived organoid models. More importantly, evaluation in a clinical cohort of lung cancer patients confirmed the model's ability to accurately reflect actual treatment responses. This study represents the first successful integration of genotype, drug structure, and organoid phenotype within a unified computational framework, significantly enhancing the accuracy and biological interpretability of drug response predictions while providing a clinically applicable tool for precision oncology in lung cancer.

The objective of this study was to investigate the protective effects and underlying mechanisms of Astragalus polysaccharide (APS) against benzene-induced DNA damage and hematopoietic toxicity. A mouse model was established through subcutaneous injection of benzene (150 mg/kg/d), while APS (100 mg/kg/d) was administered intraperitoneally for 15 days. The results indicated significant improvements in haematotoxicity: APS markedly elevated the levels of white blood cell (WBC, restored to 68 % of normal) and platelets (Plt, 67 %) in benzene-exposed mice (p < 0.05). Additionally, it alleviated femoral bone marrow luminal fibrosis and reduced haematopoietic cell counts. Furthermore, DNA damage repair was observed: Western blotting (WB) and immunohistochemistry analyses demonstrated that APS decreased the expression levels of gamma-H2AX induced by benzene (p < 0.05) as well as p21 expression (p < 0.05/p < 0.0001), thereby ameliorating DNA damage in bone marrow cells. In a model involving K562 cells subjected to damage from the benzene metabolite 1,4-BQ, APS significantly down-regulated gamma-H2AX levels (p < 0.001/p < 0.05) and p21 levels (p < 0.0001/p < 0.01). Moreover, comet assay results revealed an 86 % reduction in DNA breaks due to APS treatment (p < 0.001). Through network pharmacological analysis, it was predicted that APS exerts its protective effects against DNA damage and hematopoietic toxicity by inhibiting oxidative stress while regulating gene expressions such as TNF-alpha, STAT3, and HSP90AA1; these findings were further validated using RT-qPCR along with MDA, GSH, and GSH-Px assays. In conclusion, this study demonstrates that APS has considerable potential to mitigate benzotoxicity while providing theoretical foundations for effective therapeutic strategies or interventions aimed at addressing benzotoxicity.

Perfluorooctane sulfonate (PFOS), a widely used persistent organic pollutant, has been implicated in multiple toxicities. However, its nephrotoxic mechanisms remain unclear. Chronic kidney disease (CKD) is a growing global health concern. We adopted a multidisciplinary approach combining epidemiological analysis, network toxicology, molecular docking, and animal experiments to investigate PFOS-induced kidney injury using CKD as a model. NHANES data (n = 9119) were analyzed to examine the association between serum PFOS levels and CKD prevalence. Network toxicology identified PFOS-related target genes, which were further refined through protein-protein interaction (PPI) analysis and validated using the GSE32591 dataset. A diagnostic model was constructed, and molecular docking and in vivo studies were performed to verify gene-compound interactions and biological effects. Coremine Medical was used to identify traditional Chinese medicine (TCM) candidates targeting key genes. Serum PFOS levels were significantly associated with CKD, showing a U-shaped dose-response. Four hub genes-ALB, PTGS2, AKT1, and IGF1-were identified and used to develop a diagnostic model with excellent accuracy (AUC = 0.96). Molecular docking confirmed stable PFOS-protein interactions. PFOS exposure in mice led to dose-dependent renal tubular injury, elevated NGAL and KIM-1 levels, and PI3K-AKT pathway activation. Astragalus membranaceus, identified through TCM screening, exhibited strong binding to the target proteins and may have therapeutic potential. This study reveals key molecular targets and pathways involved in PFOS-induced nephrotoxicity and proposes a TCM-based therapeutic strategy. Our findings offer new perspectives for risk assessment and intervention in PFOS-related kidney disease.

The novel pollutant, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) leaked out of the tire and has attracted extensive concerns due to its high lethal toxicity of salmon. However, the potential hepatotoxicity of 6-PPDQ exposure and its mechanisms are unknown. As a novel 3D cell culture, liver organoids (LOs) are more similar to real organ invitro in structure and function, which showed great potential for toxicity assessment. Herein, stable LOs were generated and their applicability on hepatotoxicity assessment was evaluated with four hepatotoxic compounds. The negative effect of 6-PPDQ was explored in LOs, live/dead staining visually demonstrated the damage to the liver, and the changes of ATP, LDH, ALT, and AST effectively reflected its hepatotoxicity. Meanwhile, machine learning-based quantitative assessments of LOs morphology changes provided objective data on area, circularity, and luminance changes, enabling sensitive detection of 6-PPDQ-induced hepatotoxicity. Furthermore, transcriptomic analysis revealed that the pathways related to DNA replication and repairment, cancers, and inflammation were significantly involved in the process of 6-PPDQ-induced liver injury; Disease enrichment analysis highlighted an increased risk of chronic liver diseases, and biliary atresia were validated by Cholyl-Lys-Fluorescein (CLF). Moreover, molecular docking analysis identified potential molecular targets of 6-PPDQ, including Slc6a9, Yes1, and Nos2. This study underscored the potential of LOs for toxicological studies and highlighted the toxic effects of 6-PPDQ on the liver, suggesting the need for further investigations to understand its long-term impact on human health.