Ligusticum sinense cv. Chuanxiong (Chuanxiong) is threatened by excessive cadmium (Cd), affecting its safety and quality. This study aimed to characterize Cd distribution in Chuanxiong roots (subcellular level) and clarify its key response mechanisms to Cd stress, using ICP-MS, SEM-EDS, and transcriptome analysis. The results showed that Cd was mainly enriched in root cell walls; Cd stress significantly upregulated the activities of polyphenol oxidase (PPO, +11.50 %), cinnamyl alcohol dehydrogenase (CAD, +31.05 %), catechol O-methyltransferase (COMT, +28.28 %), and isocitrate lyase (ICL, +121.93 %) compared with the control; Cd-related genes (NRAMP5, CAX3, YSL7, etc.) and key transcription factors (BHLH162, ERF109, etc.) were markedly upregulated. Furthermore, Chuanxiong roots achieved growth-stress resistance balance (exhibiting hormesis) via the carbon metabolism pathway (the material and energy basis), the sulfur metabolism (the core detoxification pathway), and the phenylpropanoid biosynthesis (structural and chemical defense). This study provides a theoretical basis for developing precise regulatory techniques to reduce heavy metals (HMs) accumulation in medicinal plants, and thus safeguard their quality and safety.

Microplastics, as a novel environmental pollutant, are now widely distributed in agricultural soils globally and pose a threat to plant growth and development. Within apple orchards, the ageing and degradation of agricultural plastic films leads to soil microplastic contamination, inhibiting the growth of apple trees. This study employed apple rootstocks 'M9' and 'B9' alongside the apple cultivar 'Gala3', treating them with polystyrene nanoplastics (PS-NPs) at varying concentrations (0, 5, 10, 20, 40, 80 mg/L). Results indicate that low PS-NP concentrations promote apple seedling growth, whereas high concentrations inhibit root development and growth while reducing antioxidant capacity. Sensitivity to PS-NPs varies among genotypes, with 'M9' exhibiting the lowest sensitivity and 'Gala3' the highest. Based on these phenotypic differences, transcriptomic and metabolomic sequencing was performed on these two cultivars. Integrated transcriptomic-metabolomic analysis revealed that PS-NPs disrupted zeatin metabolic homeostasis by upregulating CKX gene and downregulating UGT73C gene. This accelerated the metabolism of active zeatin (e.g., trans-zeatin) and leading to dihydrozeatin (DHZ) accumulation, thereby impairing the activation capacity of the antioxidant defence system and ultimately exacerbating oxidative damage. These findings establish a foundation for systematic investigation into the molecular mechanisms underlying apple responses to nanoplastics, offering novel perspectives for future crop production and environmental safety.

In Arabidopsis (Arabidopsis thaliana), a family of 5 receptors mediates ethylene responses in roots, with Ethylene Response 1 (ETR1) controlling increases in root hair proliferation and decreases in lateral root formation. To define the ETR1-dependent gene regulatory network (GRN) controlling root development, we profiled the root transcriptome from Col-0 and the etr1-3 gain-of-function and etr1-7 loss-of-function mutants in the presence and absence of ethylene or the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC). We identified 4,522 differentially expressed (DE) transcripts in Col-0 roots that displayed altered abundance in response to ethylene and/or ACC treatment, with larger-magnitude changes induced by ethylene. These included 553 DE transcripts that were ETR1 dependent, defined by a lack of response to treatment with ethylene and/or ACC in ethylene-insensitive etr1-3 and constitutive alteration response in etr1-7 in the presence or absence of treatment relative to time-0 Col-0. These ETR1-dependent transcripts include transcripts from genes associated with ethylene biosynthesis and those encoding transcription factors (TFs). Reporter fusions driven by promoters from ACC OXIDASE 2 (ACO2) and ACO3, which convert ACC to ethylene, were regulated by ACC in root tissues in appropriate locations to control root development, with pACO5-driven GFP detected in root hairs. We examined the abundance of ETR1-dependent transcripts predicted to encode TFs and ACOs in Col-0 and an ein3 eil1 mutant, with and without ACC treatment. Our results suggested that the ETR1 and Ethylene Insensitive 3 (EIN3)/EIN3-like 1 (EIL1) canonical ethylene signaling pathway regulates some, but not all, of these transcriptional responses. Together, these findings reveal features of an ETR1-dependent GRN that controls both ethylene biosynthesis and root growth and development.

Plants reprogramme their metabolism upon pathogen attack, producing compounds that can either enhance immunity or be exploited by pathogens. Metabolomic profiling of wheat during Fusarium graminearum infection revealed pronounced accumulation of phenolamides, driven by activation of their biosynthetic pathways. Notably, exogenous N-feruloylputrescine (Ferput), a representative phenolamide, enhanced resistance to wheat stripe rust, powdery mildew and rice blast but increased susceptibility to Fusarium head blight. Ferput inhibited fungal infection in the lemma while promoting rachis colonisation, indicating pathogen- and tissue-specific effects. Mechanistic analyses showed that Ferput stimulates deoxynivalenol (DON) biosynthesis by inducing TRI gene expression, toxisome formation and DON-associated cellular differentiation, underlying the shift from lemma resistance to rachis susceptibility. Together, these findings highlight the context-dependent roles of phenolamide in plant-pathogen interactions and suggest that, under specific pathological contexts, defence-associated metabolites can be exploited by pathogens to enhance their virulence. This insight underscores the necessity of considering the dual functional roles of plant metabolites when engineering broad-spectrum disease resistance.

This study profiled physiological, biochemical, and transcriptional responses of Solanum nigrum to cadmium (Cd) in potted soil across graded treatments. Growth, assessed as fresh and dry mass, and chlorophyll a declined only at higher doses, whereas carotenoids increased by about 70%. Proline rose by roughly 302% and soluble proteins by 173% in a dose-responsive manner, consistent with up to 9.1-fold increases in P5CS transcripts. Malondialdehyde and hydrogen peroxide increased with Cd, accompanied by antioxidant responses. Shoots accumulated substantial Cd in soil, reaching 170 mg kg-1 DW at 100 mg kg-1 soil Cd, while the tolerance index remained ≥ 60% at the highest dose. The translocation factor exceeded one at all additions and peaked at ~ 1.28 at 50-100 mg kg-1Bioavailability-aware enrichment remained high: BCF_available (shoot) referenced to DTPA-Cd was ~ 19.4 at 12.5-25 mg kg-1 16.9 at 50 mg kg-1, and 12.6 at 100 mg kg-1. Whole-plant removal increased monotonically, with total Cd uptake of approximately 166, 303, 392, and 518 µg plant-1 at 12.5, 25, 50, and 100 mg kg-1, respectively. Candidate transporter transcripts showed distinct dose-dependent patterns in soil: SnYSL3 peaked at the intermediate dose (~ 7.6-fold), whereas HMA3 rose progressively and was highest at 100 mg kg-1 (~ 7.2-fold). Principal component analysis separated treatments and grouped stress markers with P5CS and HMA3 at higher Cd. This work provides a gradient-resolved, soil-based dataset linking Cd partitioning, bioavailability-normalized indices, and total uptake with coordinated shifts in candidate YSL and HMA transporters and key metabolites. The resulting framework establishes a standardized baseline for functional validation and field translation.

Armillaria species have attracted considerable research interest, because they are widely distributed, mostly plant-pathogenic, and exhibit unique characteristics. Abiotic factors influence intra- and interspecies variations in pathogenicity and/or virulence of these fungi. However, the mechanisms involved in causing these variations are not well understood. Iron is an indispensable element in several molecular and biological processes. Yet, excessive abundance of iron can be toxic to organisms due to Fenton-like reactions. This study aimed to gain insights into the type and extent of iron-responsive proteomic and secretomic changes in Armillaria sp. strain CMW4456 cultured in liquid media supplemented with iron using a multiomics approach. Significant iron-dependent alterations of proteins involved in metabolism and growth were observed in the proteomes and secretomes. Iron supplementation at 100 μM did not elicit an oxidative stress response by the fungus. Our analyses revealed three putative siderophore biosynthetic gene clusters (BGCs) in the genome and expression of proteins encoded by some BGC genes in the proteome. This knowledge contributes to a better understanding of the mechanisms employed by an Armillaria sp. in response to iron, gives insights into possible modes for inhibiting or attenuating the pathogenicity and/or virulence of Armillaria spp., and can be valorized for more biotechnological applications.

Amblyopia is a neurodevelopmental disorder, and there are no effective treatment methods for adult amblyopia patients due to the decline in synaptic plasticity in visual cortex. Enriched environment (EE) has been shown to enhance synaptic plasticity, which is mediated, at least in part, by epigenetic mechanisms involving histone acetylation. This study aims to investigate whether histone deacetylase (HDAC) inhibitors can replicate the effects of EE on visual cortical plasticity, thereby offering novel therapeutic insights for adult amblyopia. First, we established adult amblyopia mice model, which were then randomized into five groups: untreated amblyopia, standard housing, EE, vehicle, trichostatin A (TSA) groups, with normal mice serving as controls. To evaluate synaptic plasticity in visual cortex, we measured synaptic marker VGLUT2, synaptic ultrastructure and long-term potentiation (LTP). Additionally, biochemical analyses were conducted to measure alterations of HDACs associated with synaptic integrity. Our findings revealed that EE enhanced synaptic plasticity in visual cortex of adult amblyopia mice and was associated with reduced HDAC3 expression. Similarly, the broad HDAC inhibitor TSA, improved synaptic ultrastructure, increased VGLUT2 expression, and potentiated LTP, functionally resembling several key effects of EE. Importantly, TSA targets multiple HDAC isoforms, and the observed reduction in HDAC3 levels is correlated with, but does not establish, a causal role for HDAC3. These results indicate that broad HDAC inhibition can mimic EE-induced plasticity in adult amblyopia, while highlighting the need for selective HDAC3-targeted approaches to determine mechanistic specificity. Overall, our study provides a foundation for developing epigenetic-based strategies to enhance adult visual cortical plasticity.

Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication following anesthesia and surgery. Recent evidence has implicated dysregulation of cerebral iron metabolism in the pathogenesis of this condition. Our previous studies have demonstrated that sevoflurane anesthesia disrupts iron homeostasis, ultimately leading to POCD. Hepcidin plays a crucial role in maintaining systemic iron homeostasis. The JAK2-STAT3 signaling pathway is essential for hepcidin transcription. According to earlier research, microRNA-135b-5p (miR-135b-5p) targets JAK2 to suppress the JAK2-STAT3 pathway. However, little is currently known about how miR-135b-5p contributes to the dysregulation of iron metabolism induced by sevoflurane. This study sought to determine whether miR-135b-5p reduces sevoflurane-induced POCD by inhibiting the JAK2-STAT3 pathway, thereby lowering hepcidin production.

Gastric cancer (GC) remains among the cancers with extremely high morbidity and mortality rates worldwide, and chemotherapy resistance limits its therapeutic efficacy. Therapy‑induced senescence (TIS) is vital for inducing chemotherapy resistance and promoting tumor progression, highlighting the need to explore its regulatory mechanisms. To investigate oxaliplatin (OXA)‑induced senescence in GC cells, cellular senescence was assessed by senescence‑associated β‑galactosidase (SA‑β‑Gal) staining, western blotting, immunofluorescence, and reverse transcription‑quantitative polymerase chain reaction for the senescence‑associated secretory phenotype (SASP) factors. Moreover, multi‑omics integration including transcriptomic, proteomic and untargeted metabolomic, was used to identify key regulators and pathways. OXA induced a senescent phenotype characterized by p21 upregulation, SA‑β‑Gal staining, cell cycle arrest and SASP secretion. Integrative multi‑omics analysis revealed that NR4A1 is a central upstream regulator, and the PI3K/AKT pathway is suppressed in OXA‑induced senescence. Notably, survival analysis verified that NR4A1 expression was correlated with the prognosis of patients in GC. Functional studies demonstrated that NR4A1 knockdown attenuated OXA‑induced senescence, restored PI3K/AKT activity, and reduced SASP expression. Metabolomic profiling revealed that OXA‑induced senescence induced metabolic reprogramming, including glycolysis enhancement and oxidative phosphorylation suppression. Notably, NR4A1 knockdown reversed these metabolic alterations. The present study identified NR4A1 as a key regulated gene in chemotherapy‑induced senescence in GC and verified that the NR4A1/AKT‑metabolism axis is vital for the pivotal mechanism of TIS. These findings may provide a novel therapeutic strategy to optimize chemotherapy and develop 'one‑two punch' approaches targeting senescent tumor cells.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder with no approved therapeutics targeting the disease mechanism. DM1 is caused by the expression of expanded CUG repeat RNA (CUGexp), which sequester the muscleblind-like (MBNL) family of RNA binding proteins leading to dysregulated alternative splicing and a host of downstream impacts. While previous studies showed that diamidines rescued DM1 dysregulated alternative splicing events, their potential was limited by toxicity and off-target effects. A new class of modified polycyclic compounds (MPCs), based on diamidines, were created and screened in DM1 patient-derived cell lines. This approach identified MPC03 and MPC04 as being capable of rescuing DM1 dysregulated splicing events at low nanomolar concentrations with no obvious toxicity and limited off-target effects. In a DM1 mouse model, treatment with MPC03 and MPC04 reduced CUGexp RNA levels and partially rescued DM1 mis-splicing. Binding data and modeling showed that lead MPCs bind to CUGexp RNA, and in cells lacking CUG repeats, MPC activity was absent, suggesting that these compounds displace sequestered MBNL proteins from CUGexp RNA. Taken together, MPCs show therapeutic promise across multiple DM1 models.

Xizang sheep are vital economic livestock in plateau regions. Traditional surgical castration often induces stress and infection. Although immunization presents an alternative method, the physiological mechanisms underlying its effects in Xizang sheep remain unclear. Therefore, this study integrated serum immune-antioxidant indicators with hypothalamus-pituitary transcriptomics to investigate molecular mechanisms of GnRH immunization. Results indicated that serum IgA, IgG, IgM, SOD, and GSH in the immunization (IM) group were significantly higher than in control (CON) and surgical castration (SN) groups, while IL-6 and TNF-α were significantly reduced (p < 0.05). RNA-seq analysis revealed that hypothalamic CYTB, ATP6, COX, ABLIM1, and ABI3 were significantly upregulated in IM group, whereas SHISA7 and PTPRO were significantly downregulated, with notable enrichment in prion disease, oxidative phosphorylation, and thermogenesis pathways. Pituitary RPL15 was upregulated while RPL10A, CACNA1D, ANK1, DDX3X, and KCNMA1 were significantly downregulated, showing enrichment in myofibril, contractile fiber, sarcomere, and cytosolic ribosome pathways. Association analysis revealed significant positive correlations between IgG and pituitary ATP6, CYTB, TNNI2, as well as hypothalamic COX1, COX, and ND4. In summary, GnRH immunization outperforms surgical castration by modulating hypothalamic-pituitary genes and enhancing immunity and antioxidants in plateau Xizang sheep, achieving integrated neuroendocrine-immune regulation for healthy husbandry of plateau Xizang sheep.

Nitric oxide (NO) is a key signaling molecule that plays a vital role in maintaining homeostasis of physiological processes such as immune responses and neurotransmission. However, excessive NO production during inflammatory responses to infection can lead to cytotoxicity and tissue damage. The nasal epithelial barrier is a crucial first line of immunological defense against viral infections, and it is likely exposed to excessive NO levels during chronic inflammation. Therefore, clarifying the effects of NO on this barrier is thus critical. In this study, we investigated the biological effects of sustained NO exposure on RPMI2650 human nasal epithelial cells. Post-NO exposure transcriptomic analyses revealed significant upregulation of genes involved in the p53 signaling pathway. RT-qPCR analyses confirmed the temporal upregulation of p53 target genes associated with apoptosis and cell cycle regulation. These gene expression changes downregulated cell proliferation and induced cell death. Our findings suggest that excessive NO exposure induces nasal epithelial cell death via the p53 pathway, which over the long term can result in tissue damage and dysfunction under inflammatory conditions. These results provide new insights into how prolonged NO exposure affects the nasal epithelial cells and may contribute to the progression of chronic infectious diseases.

Activation of hypoxia-inducible factors (HIFs) supports cancer cell survival, yet how HIFs govern cell death remains unclear, despite evidence that HIF-1 acts as a tumor suppressor in cell renal cell carcinoma (ccRCC). Here, we report a cell death-priming role for HIF-1/2 in ccRCC. Through cell viability screens with chemical libraries, we identify SGI1027 and its analog MS1129 as HIF-1/2-dependent cell death inducers that specifically kill VHL-deficient ccRCC cells in vitro and patient-derived xenografts in mice. Mechanistically, SGI1027 and MS1129 induce proteasomal degradation of DNMT1/DNMT3A/DNMT3B proteins, leading to the loss of promoter methylation and subsequent upregulation of TRAIL, DR4, and DR5 in ccRCC cells. HIF-1/2 induces procaspase-10 expression serving a commitment point to activate TRAIL-induced apoptosis in VHL-deficient ccRCC following SGI1027 or MS1129 treatment. Notably, recombinant TRAIL protein synergizes with SGI1027 or MS1129 to kill VHL-deficient ccRCC in mice. Collectively, our study unveils an apoptosis induction strategy that involves hijacking HIFs for ccRCC treatment.

Osteoarthritis (OA) is a prevalent degenerative joint disease with no curative treatment currently available. Recent evidence suggests that chondrocyte ferroptosis contributes to OA progression. Chondroitin sulfate (CS), widely used in OA management, exhibits anti-inflammatory and antioxidant properties, yet its role in modulating ferroptosis remains unclear. In this study, we investigated whether CS alleviates OA by inhibiting chondrocyte ferroptosis and explored the underlying mechanisms. Using an in vitro ferroptosis model induced by RSL3 in rat chondrocytes, we found that CS significantly restored cell viability and ameliorated ferroptosis-related changes, including reduction of intracellular and mitochondrial ROS, lipid peroxidation, and iron overload. CS also downregulated the expression of ferroptosis markers PTGS2 and ACSL4, while upregulating SLC7A11 and HSPA8 in a dose-dependent manner. Network pharmacology and transcriptomic analysis identified HSPA8 as a key overlapping gene among CS targets, OA-related differentially expressed genes, and ferroptosis-related genes. In a rat OA model induced by modified Hulth surgery, CS treatment attenuated cartilage degradation, as evidenced by improved OARSI scores, restored COL2A1 expression, and suppressed MMP13. Immunohistochemistry confirmed that CS upregulated SLC7A11 and HSPA8 while downregulating ACSL4. These findings demonstrate that CS mitigates OA progression by inhibiting chondrocyte ferroptosis, potentially through upregulation of HSPA8 and subsequent enhancement of SLC7A11 expression. Our study provides novel insights into the mechanism of CS in OA treatment and highlights ferroptosis as a promising therapeutic target.

Bone fracture healing is a multifaceted process that involves different stages and intercellular interactions. In this study, we aimed to investigate the effect of Taohong Siwu decoction (TSD) on bone fracture healing and the underlying mechanisms.

The addition of CDK4/6 inhibitors to endocrine therapy has significantly improved outcomes in HR+/HER2- breast cancer (BC). However, variable patient responses and acquired resistance remain a clinical challenge. We therefore defined the comprehensive molecular response to palbociclib, the most clinically used CDK4/6 inhibitor. Global analyses of gene expression, protein abundance, splicing, and chromatin accessibility revealed broad patterns and specific changes that result from CDK4/6-inhibition in BC cells. We uncovered unexpected feedback between CDK4/6 and estrogen-response signaling, which has clear clinical implications. We also revealed a widespread alternative splicing program that partially overlapped with genes whose expression is regulated, and which is expected to impact protein function. These molecular changes nominated combination therapies that interfere with the activation of CDKs or ERα. Accordingly, co-targeting CDK7, which regulates CDK2, CDK4/6, and ERα, additively impacted cell fitness. Collectively, these data reveal a complex, multitiered response to CDK4/6 inhibition, with implications for therapeutic efficacy.

Despite mounting evidence that commensal microbes enhance host defenses, whether and how they directly suppress pathogen virulence remains elusive. Here, we investigate metabolites from the gut microbiota of infection‑resistant Tibetan chickens for their ability to reduce Salmonella virulence gene expression and elucidate the molecular mechanism by which these compounds inhibit the LuxS/AI‑2 quorum‑sensing system.

Transforming growth factor (TGF)-β1 is a pro-fibrotic cytokine that affects extracellular matrix (ECM) deposition and fibroblast activity. 17β-Estradiol (E2), the dominant ovarian steroid during the follicular phase (FLP) of the estrous cycle, can also influence ECM remodeling and fibrosis, through prostaglandin (PG) synthesis. PGs have opposing roles in fibrosis, with PGE₂ showing anti-fibrotic effects and PGF₂α promoting fibrosis. Equine endometrosis, whose main pathological feature is fibrosis, is marked by chronic inflammation and ECM accumulation, and may involve mediators like TGF-β1, PGs, and E2. This study aimed to assess how TGF-β1, E2, and their combination affect PG synthase and receptors transcription (qPCR) and PG concentrations (ELISA) in equine endometrial explants during the FLP, after 24 and 48 h. Prostaglandin-endoperoxide synthase 2 (PTGS-2) mRNA was reduced with TGF-β1 and combination treatments at 24 h. Estradiol and combined treatments downregulated microsomal prostaglandin E synthase1 (PGES) mRNA at 24 h, while prostaglandin F synthase (PGFS) mRNA reduced with TGF-β1 at 24 h and with E2 at 48 h. The PGE₂ concentration was lower in TGF-β1 +E2 group than in controls and TGF-β1 alone at 48 h. In contrast, PGF₂α concentration increased with E2 at 24 h and TGF-β1 and TGF-β1 +E2 treatments at 48 h. Prostaglandin E receptor (EP)2 and 4 mRNA upregulated with the combination treatment, while prostaglandin F receptor (FP) mRNA decreased in all treated groups. These findings suggest that TGF-β1 and E2 interact to regulate PG pathways, with potential to drive fibrotic changes in the equine endometrium, by shifting the balance between anti- and pro-fibrotic mediators like PGE₂ and PGF₂α.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants increasingly linked to human disease. Perfluorohexanesulfonic acid (PFHxS), a widespread PFAS detected in human serum, has an uncharacterized role in gastric cancer (GC), one of the leading causes of cancer mortality worldwide. Here, we employed an integrated multi-omics approach combining network toxicology, large-scale transcriptomic analyses from TCGA and GEO cohorts, single-cell RNA sequencing, and molecular simulations, followed by in vitro and in vivo validation at environmentally relevant concentrations. We identified 667 common targets of PFHxS and GC and developed an 11-gene gradient boosting machine (GBM) prognostic signature that robustly stratified patient survival across independent cohorts and correlated with distinct tumor immune microenvironments. Mechanistically, PFHxS was predicted and experimentally confirmed to directly bind Kelch-like ECH-associated protein 1 (KEAP1), a key regulator of oxidative stress. Chronic low-dose PFHxS exposure downregulated KEAP1 protein expression, disrupted KEAP1/NRF2 antioxidant signaling, and promoted GC cell proliferation, migration, invasion, and tumor growth in vivo. Together, these findings provide the first molecular evidence that PFHxS acts as an environmental driver of GC progression by targeting KEAP1, while also delivering a clinically relevant prognostic tool. This work highlights a previously unrecognized environmental risk factor for gastric cancer and offers new perspectives for risk assessment, prevention, and therapeutic intervention.

Emerging environmental health issues posed by micro- and nanoplastics (M/NPs) have raised significant concerns. Accumulating evidence suggested that M/NPs can bioaccumulate in gonads and impair fertility in animals, yet the underlying cellular mechanisms and tissue-specific responses remain poorly understood. In this study, we employed in vivo and in vitro models to systematically investigate the impact of polystyrene micro- and nanoplastics (PS-M/NPs, 100 nm and 5 µm) on ovarian development and function in pubertal female mice. Following 35-day exposure, we observed size-dependent reproductive toxicity, with 100 nm PS-NPs causing reduced body weight gain and ovarian size, disrupted folliculogenesis, and altered hormone levels. Leveraging single-cell RNA-sequencing (scRNA-seq), we uncovered profound alterations in intracellular communication networks across seven ovarian cell types. Granulosa cells (GCs) were identified as the primary target of PS-NPs, exhibiting marked transcriptional changes, including dysregulation of FSCN1, a critical actin cytoskeleton regulator. In vitro experiments confirmed that only 100 nm PS-NPs were internalized by GCs, leading to cell cycle arrest, necroptosis, and hormonal dysfunction. Mechanistically, PS-NPs triggered F-actin cytoskeleton remodeling, increasing cell stiffness and histone modifications (H3K4me3, H3K27ac) associated with chromatin accessibility. Integrated ATAC-seq and RNA-seq analyses implicated STAT1 as a key transcriptional regulator driving PS-NP-induced epigenetic and transcriptional changes. Overall, our findings establish the first single-cell resolution atlas of PS-NP-mediated ovarian toxicity, revealing that NPs disrupt reproduction through cytoskeletal damage and epigenetic reprogramming. This work provides unprecedented insights into the molecular and epigenetic consequences of M/NPs in mammalian reproduction, emphasizing the potential health risks of environmental M/NP exposure.