Glioblastoma (GBM) is a highly aggressive malignant tumor of the central nervous system, and resistance to temozolomide (TMZ) remains a major cause of treatment failure and tumor recurrence. DNA damage repair (DDR) serves as a critical mechanism underlying chemoresistance, with replication factor C4 (RFC4) emerging as a key mediator. We aimed to investigate the mechanism by which RFC4 induces TMZ resistance in GBM through DDR activation. Analysis of clinical specimens revealed that RFC4 is overexpressed in glioma tissues and correlates with poor prognosis in patients with GBM. Functional assays in vitro and in vivo demonstrated that RFC4 knockdown significantly inhibits GBM cell proliferation, invasion, and migration, while concurrently enhancing TMZ sensitivity. Bioinformatic analysis identified checkpoint kinase 1 (CHK1) as a key downstream effector of RFC4. Mechanistic studies further showed that RFC4 promotes DDR activation through a synergistic interaction with CHK1, thereby diminishing cellular sensitivity to TMZ. Notably, CHK1 inhibition effectively reversed RFC4-mediated TMZ resistance. Collectively, these findings indicate that RFC4 functions as an oncogenic driver in GBM by stabilizing CHK1 and enhancing DNA repair. Targeting RFC4 to modulate DDR may therefore represent a promising therapeutic strategy to overcome TMZ resistance and improve outcomes for patients with GBM.

Micro- and nano-plastics have emerged as widespread environmental pollutants, with growing concerns regarding their impact on human health. Polystyrene nanoplastics (PS-NPs) accumulate in the alveolar region and have been implicated in the development of pulmonary fibrosis. However, the underlying mechanisms by through which PS-NPs promote fibrotic lung disease remain poorly understood. Macrophages are closely associated with both inflammation and fibrosis progression, which are central players in the pulmonary response to environmental insults. This study aimed to determine whether PS-NPs activated pulmonary macrophages to induce lung fibrosis. We demonstrated that bronchial exposure to PS-NPs induced pulmonary fibrosis, accompanied by robust inflammatory responses and pro-inflammatory activation of monocyte-derived macrophages (MoMs) in vivo. The pro-resolving mediator resolvin D1 effectively ameliorated PS-NP-induced fibrosis by attenuating inflammation and inhibiting the secretion of pro-inflammatory cytokines from MoMs. PS-NPs activated MoMs to promote fibroblast-to-myofibroblast differentiation via an oxidative-stress-dependent mechanism involving IL-6 secretion in vitro. Mechanistically, PS-NPs triggered the unfolded protein response (UPR) activation in MoMs, which drove oxidative-stress-dependent IL-6 secretion and promoted fibroblast-to-myofibroblast differentiation. The PERK arm was identified as the predominant UPR pathway and it initiated a critical PERK/oxidative-stress/IL-6 signaling axis in the MoMs. Importantly, IL-6 deficiency (IL-6-/- mice) and IL-6 neutralization significantly suppressed PS-NP-induced lung inflammation and fibrosis, highlighting the essential role of macrophage-derived IL-6 in this process. In conclusion, PS-NPs drive pulmonary fibrosis by activating the UPR/oxidative-stress/IL-6 signaling axis in MoMs. These findings highlight IL-6 as a potential therapeutic target for the prevention of environmental-insult-related fibrotic lung disease.

Terpenoids represent an extensive class of natural compounds with significant biological activities. Consequently, identifying the genes implicated in their synthesis is crucial for advancements in agricultural and medicinal applications. To elucidate the regulatory role of the DXR gene in terpenoid biosynthesis, three genes encoding PgDXR (PgDXR1-PgDXR3) were identified from Platycodon grandiflorus. Quantitative real-time PCR analysis revealed that PgDXR genes were widely expressed across various tissues, and PgDXR genes exhibit significant transcriptional responses to drought (PEG6000), abscisic acid (ABA), salicylic acid (SA), and methyl jasmonate (MeJA) treatments. Subcellular localization studies demonstrated that PgDXR proteins are localized to distinct subcellular compartments (PgDXR1 in chloroplasts; PgDXR2/3 in nucleus and cytoplasm). Phylogenetic analysis indicated that PgDXR1 may play a crucial role in triterpenoid saponin metabolism. Furthermore, both in situ hybridization and Western blot analysis indicated that PgDXR1 (mRNA and protein) expression is highest in the roots of two-year-old P. grandiflorum plants. We further analyzed the biological functions of PgDXR1 in triterpenoid saponin synthesis both in vitro and in vivo. Yeast one-hybrid (Y1H) assays demonstrated that MYB39 binds to the PgDXR1 promoter, while dual-luciferase (LUC) assays confirmed that MYB39 transcriptionally activates PgDXR1. This study lays a foundation for further elucidating the molecular regulatory mechanism of terpenoid synthesis in P. grandiflorum and provides a reference for understanding the biological functions of the DXR.

Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 10% to 25% of intrahepatic cholangiocarcinoma (iCCA) cases. Despite significantly prolonged progression-free survival, the mutant IDH1 (mIDH1) inhibitor ivosidenib achieved only a 3% response rate in clinical trials, highlighting the need for new therapeutic options for IDH1 mutation (IDH1mut) iCCA. Our in silico analysis demonstrated that IDH1mut and TP53 mutation (TP53mut) were mutually exclusive in iCCA cells and that IDH1mut iCCA cells expressed higher mouse double minute 2 homolog (MDM2) levels than IDH1wt iCCA cells. Chromatin immunoprecipitation quantitative polymerase chain reaction assay showed enrichment of histone-3-lysine-4 tri-methylation (H3K4me3), an indicator of active gene transcription, at the MDM2 promoter in IDH1mut iCCA cells, confirming the data from ENCODE histone-seq. Treatment with a mIDH1 inhibitor reduced 2-hydroxyglutarate (2-HG) levels, enhanced lysine-specific demethylase 5 (KDM5) activity, and attenuated the H3K4me3/H3K4me1 ratio at the MDM2 promoter, which was accompanied by a reduction in MDM2 expression and an increase in wild-type TP53 (wtTP53) protein levels in IDH1mut iCCA cells. The effect of the mIDH1 inhibitor on MDM2 mRNA levels was reversed by treatment with KDOAM-25 citrate, a pan-KDM5 inhibitor. In addition, MDM2 inhibitors that could block MDM2-mediated wtTP53 degradation selectively induced TP53 reactivation, cell-cycle arrest, and growth inhibition in IDH1mut iCCA cells. The combination of mIDH1 and MDM2 inhibitors synergistically suppressed the proliferation of IDH1mut iCCA cells. Our study delineated a novel mIDH1-MDM2-wtTP53 axis and its potential application for wtTP53 reactivation therapy in IDH1mut iCCA.

Epigenetic clocks are commonly used aging biomarkers based on DNA methylation that predict long-term morbidity and mortality risk. Increased cellular senescence with age is also posited to contribute to age-related disease and mortality. However, prior studies have found that existing epigenetic clocks show inconsistent associations with cellular senescence and no reductions after senolytic treatment. We hypothesize this reflects that senescence-related CpGs are a small proportion of age-related CpGs, and that an epigenetic clock focused on a core senescence signal conserved across different cell types and different senescence inducers would be a better tool for monitoring senescence and senolytic treatment compared to traditional epigenetic clocks. In our study, we find that senescence, age and mortality risk intersect at a small subset of the DNA methylome (9363 CpGs out of 396,333 analyzed; 2.4%). Utilizing these CpGs, we generated three different epigenetic clocks trained to predict in vitro senescence, age, and mortality, respectively. Surprisingly, all three of these predictors stayed the same or even accelerated after senolytic treatment in both in vivo and in vitro data. Our findings not only call into question whether cellular senescence can be captured by DNA methylation but also challenge the assumption that aging biomarkers decrease after geroscience interventions.

Metabolic stress caused by lipid overload is a key driver of cellular dysfunction in aging and disease. Excess saturated fatty acids such as palmitate impair fatty acid oxidation (FAO), promote lipid accumulation, and increase reactive oxygen species (ROS), ultimately triggering premature senescence-like states. Senescence further amplifies vulnerability by worsening mitochondrial dysfunction, enhancing lipid imbalance, and sustaining pro-inflammatory signaling. Here, we investigated the role of the neuron-enriched RNA-binding protein HuD (ELAVL4) in protecting cells against lipotoxic stress. Using Neuro2a neuroblastoma cells, we found that HuD knockdown suppressed FAO, leading to increased lipid accumulation and elevated ROS following palmitate exposure. HuD-deficient cells also exhibited cytosolic mitochondrial DNA release, IRF phosphorylation, and upregulation of senescence markers. Mechanistically, RNA immunoprecipitation revealed that HuD binds directly to PPARα mRNA, sustaining its expression by competing with the PPARα-targeting microRNAs miR-9-5p and miR-22-3p. Loss of HuD reduced PPARα levels, thereby weakening the FAO capacity and sensitizing cells to palmitate-induced lipotoxic stress. These findings identify a previously unrecognized HuD-PPARα-FAO axis that restrains metabolic stress and senescence. By linking post-transcriptional regulation to lipid metabolism and inflammatory signaling, this work highlights stress-induced premature senescence as both an outcome and a propagator of metabolic dysfunction, providing insight into mechanisms of aging-related vulnerability.

Plants are susceptible to various environmental stresses, but basic leucine zipper (bZIP) transcription factors play a key role in regulating stress responses. In this study, a drought response-related candidate gene (ZmbZIP92) was cloned from maize (Zea mays L.) following a comparative genomic analysis. This gene is highly homologous to the rice (Oryza sativa L.) gene OsbZIP62, exhibits tissue-specific expression patterns, and is significantly induced by drought, high salinity, and abscisic acid (ABA) treatments. Subcellular localization revealed that ZmbZIP92 is a nuclear protein. Additionally, yeast-based assays of ZmbZIP92 detected a lack of transcriptional self-activation. Dual-luciferase reporter assays demonstrated that ZmbZIP92 binds specifically to the G-box (CACGTG) cis-element. Overexpressing ZmbZIP92 in Arabidopsis thaliana significantly promoted root elongation, enhanced drought tolerance, and increased sensitivity to ABA, which was reflected by markedly inhibited seed germination. RNA sequencing and differential expression analyses indicated that multiple stress response-related pathways were enriched in ZmbZIP92-overexpressing plants, including ABA signaling, antioxidant response, transmembrane transport, and general plant signal transduction pathways. In summary, ZmbZIP92 positively regulates drought tolerance through its effects on the ABA signaling pathway and other stress response-related signaling networks.

Treatment based on BRAF/MEK kinase inhibitors is one of the most commonly used methods in advanced melanoma therapy, but patients often develop resistance to treatment. Treatment-resistant cells can affect other cancer cells and the tumor microenvironment through the factors that they secrete. Therefore, this study aimed to examine the protein composition of the secretome of cells resistant to vemurafenib (a BRAF inhibitor) and cobimetinib (a MEK inhibitor) and to compare it with that of nonresistant cells. Proteomic analysis, followed by gene ontology (GO) analysis, identified many differences in resistant melanoma cells' secretomes compared to controls (nonresistant). Many proteins upregulated in resistant melanoma cells compared to their nonresistant variants were directly related to cancer progression and associated with cell adhesion, actin cytoskeleton, matrix organization, proteolysis, and drug resistance. Proteins secreted by resistant melanoma cells can undoubtedly influence the surrounding microenvironment in a way that promotes the formation of a pro-tumor niche. Among the proteins secreted in significantly higher amounts by resistant cells (compared to the control group), which may be potential biomarkers or therapeutic targets in melanoma, plasminogen activator inhibitor 1, thymosin beta-4, clusterin, interleukin-6, superoxide dismutase, and selected matrix metalloproteinases can be distinguished.

Colorectal cancer (CRC) is one of the most prevalent and deadly cancers worldwide, with late-stage diagnosis often associated with poor prognosis. The natural compound narirutin has shown various biological activities, including anti-inflammatory and anti-cancer effects, indicating its potential clinical application. This study aims to identify the key targets and potential mechanisms of narirutin treatment in colorectal cancer (CRC) through comprehensive bioinformatics analysis and machine learning methods, emphasizing its importance as a potential therapeutic agent. We utilized SwissTargetPrediction to identify 23 target genes of narirutin, followed by differential expression analysis of 3,338 genes from the TCGA-COAD dataset. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on the intersecting genes, and machine learning techniques to identify hub genes. Additionally, we conducted molecular docking studies and immune infiltration analyses. Our findings revealed that narirutin targets key genes, including ABCC1, ABCG2, CA12, EPHX2, and PTGS1, which are significantly involved in CRC progression. Enrichment analyses indicated that these genes participate in crucial pathways related to drug metabolism and immune response. Molecular docking results demonstrated favorable binding affinities between narirutin and its target proteins. Furthermore, immune cell infiltration analysis showed significant differences in various immune cell types between CRC and control groups, suggesting their role in tumor microenvironment dynamics. Narirutin may play a vital role in CRC treatment by modulating key genes and pathways, underscoring its potential as a therapeutic agent. Future studies should explore its clinical applicability and mechanisms further.

Resistance to paclitaxel-based chemotherapy represents a major clinic challenge in triple-negative breast cancer (TNBC). Insights on the regulation genes of chemoresistance and underlying mechanisms in TNBC are waiting for in-depth investigation to address the current treatment bottlenecks. In this study, we identified that ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1) was preferentially overexpressed in TNBC and correlated with worse prognosis as well as poor response to chemotherapy. Upregulation of UCH-L1 attenuated the inhibitory effect of paclitaxel on tumor cells through modulating the aerobic glycolysis, while knockdown of UCH-L1 increased the responsiveness of TNBC cells to the drug both in vitro and in vivo. Coimmunoprecipitation results revealed that the N terminal of UCH-L1 interacts with the C-terminal domain of pyruvate kinase M2 (PKM2). UCH-L1 stabilized PKM2 via removing K48-linked polyubiquitination of PKM2 protein at K498, and thereby promoting glycolysis. Moreover, the expression levels of UCH-L1 and PKM2 were elevated in paclitaxel-resistant TNBC cells, and inhibition of UCH-L1/PKM2 axis-mediated glycolysis markedly sensitized the cells to paclitaxel treatment. Meanwhile, high expression of PKM2 was associated with shorter overall survival in TNBC patients who received chemotherapy. Clinically, PKM2 expression is positively correlated with the expression of UCH-L1 in TNBC tissues. In conclusion, our study reveals that high-expressed UCH-L1 was one of the biomarkers predicting and determining chemosensitivities of TNBC by advancing the cleavage of K48-linked polyubiquitin chains from PKM2 and enhancing glycolysis, and suggests that targeting UCH-L1/PKM2 axis holds great promise for reversing chemoresistance.

Lower urinary tract dysfunction (LUTD) increases with age and disproportionately affects women, yet the molecular mechanisms underlying this sex bias remain poorly defined. The aging bladder plays a central role in this decline, and our previous work identified increased cellular senescence, oxidative stress, and activation of the PERK arm of the unfolded protein response (UPR) as key features of bladder aging. In this study, conducted as part of the NIH Common Fund SenNet program to investigate cellular senescence in mice, we explored the therapeutic potential of a senolytic drug combination of Dasatinib and Quercetin (D&Q) in male and female aged (25-month-old) bladders from genetically diverse Diversity Outbred mice. We first assessed sex differences in aged bladders (>20 months of age), then evaluated whether D&Q treatment could improve bladder health by modulating ER stress. We identified significant baseline sex differences in UPR and ER-associated degradation (ERAD) proteins, with higher expression of PERK pathway ER stress components in females and more efficient ERAD and autophagy flux in males. While D&Q did not broadly alter ER stress or autophagy markers, it selectively increased ERAD markers in females. D&Q also enhanced uroplakin expression and urothelial thickness in aged females, suggesting potential benefit to urothelial integrity. These findings suggest a potential sex-specific regulatory mechanism within the UPR pathway that may contribute to the increased vulnerability of aged females to bladder dysfunction.

Biofilms formed by Pseudomonas aeruginosa pose major challenges in both clinical and environmental settings, highlighting the need for effective control strategies. This study investigates the anti-biofilm activity of the green microalga Chlorococcum dorsiventrale against Pseudomonas aeruginosa PAO1 and the clinical isolate MUC-N1 under Luria-Bertani (LB) and Modified Biofilm Broth (MBB) conditions. Extracts prepared with acetone, cyclohexane, ethanol, methyl tetrahydrofuran (MTHF), and distilled water (50 μg/mL) were tested for their ability to inhibit biofilm formation. Acetone and ethanol extracts showed the highest activity against PAO1 in LB (63.1% and 68.6% inhibition), whereas MTHF and acetone were the most effective in MBB. For MUC-N1, aqueous and ethanol extracts inhibited biofilm formation by 86.9% and 66.3% in LB, while cyclohexane and MTHF extracts showed the highest activity in MBB. CFU counts confirmed a significant reduction in bacterial adhesion, reaching up to 84.4%. qPCR analysis revealed downregulation of the quorum sensing genes rhlI, rhlR, and mvfR in both strains, with lasI and lasR downregulated in PAO1 but overexpressed in MUC-N1. These findings suggest that C. dorsiventrale extracts disrupt bacterial communication, thereby modulating biofilm formation and the production of virulence factors.

Substitute for perfluorooctanoic acid (PFOA), like hexafluoropropylene oxide trimer acid (HFPO-TA), are sparking growing environmental and health worries because of their persistence and capacity for bioaccumulation. Here, we employed an integrated multi-omics approach to systematically investigate HFPO-TA-induced hepatic lipid metabolic dysregulation in zebrafish. Exposed to a series of concentrations (0, 5, 50, 500 μg/L) of HFPO-TA induced hepatic lipid accumulation and significantly elevated serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). Integrated transcriptomic and epigenome analyses revealed that HFPO-TA reprogrammed the hepatic epigenome by selectively activating lipid synthesis-associated enhancers while suppressing lipid oxidation pathways, predisposing to metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, HFPO-TA preferentially remodeled chromatin accessibility and distal enhancers, driving lipogenic gene activation through nuclear receptors, such as peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR). Finally, functions of PPARα and FXR in HFPO‑TA‑induced lipid imbalance were validated by pharmacological modulators. Overall, our study delivers comprehensive evidence connecting PFOA alternatives to epigenetically driven hepatic steatosis, providing mechanistic understanding to support environmental risk evaluations of emerging perfluoroalkyl and polyfluoroalkyl substances (PFAS) compounds.

Normal fertilization triggers Ca2+ oscillations in the oocyte cytoplasm. Different assisted oocyte activation (AOA) protocols differ markedly in the calcium dynamics, yet their respective impacts on embryo gene expression remain incompletely understood. In this study, we employed strontium chloride (SrCl2), which induces Ca2+ oscillations, A-23187, which induces a single Ca2+ rise, and RO-3306, which activates oocytes without a Ca2+ rise by directly inhibiting CDK1 activity, to estimate the effect of different parthenogenetic activation protocols on embryo gene expression using fertilized embryos as a control. We compared the data of omics among different blastocysts. The transcriptional profiles of diverse parthenogenetic blastocysts were distinct from those of normal blastocysts, while transcriptional levels among different parthenogenetic blastocysts were relatively similar. Similarly, proteomics analysis revealed different protein expression profiles of diverse parthenogenetic blastocysts compared to those of normal blastocysts, especially proteins related to fatty acid biosynthesis, fatty acid β-oxidation metabolic, mitochondria, RNA splicing, and RNA binding. Some protein expression differences were also observed among different parthenogenetic blastocysts. However, all parthenogenetic blastocysts exhibited similar differentially expressed pathways. Our results show that gene expression in parthenogenetic embryos is distinct from that of normally fertilized embryos, and Ca2+ rise, especially Ca2+ oscillation, is important for proper gene expression in early embryos.

Cyclic nucleotide-gated channels (CNGCs) are evolutionarily conserved calcium-permeable non-selective cation channels that play critical regulatory roles in plant abiotic stress responses. This study characterizes HcCNGC11 in kenaf (Hibiscus cannabinus L.) through integrated genomic and functional analyses. Subcellular localization analysis using GFP-fusion constructs confirmed plasma membrane-specific targeting of HcCNGC11. Tissue-specific expression profiling revealed that HcCNGC11 transcripts accumulate predominantly in roots (2.8-fold higher than leaves), followed by leaves, stems, flowers, and seeds. Notably, HcCNGC11 demonstrated rapid transcriptional upregulation under 150 mM NaCl stress, reaching maximum induction at 3 h post-treatment. Virus-induced gene silencing of HcCNGC11 significantly inhibited kenaf growth under salt stress. Biochemical analyses of the silenced lines showed 5-66% reduced activities of antioxidant enzymes (SOD, POD, CAT), decreased osmoregulatory substances (soluble protein, proline), reduced chlorophyll content, and elevated ROS (H₂O₂, O₂·⁻) accumulation. Under salt stress, HcCNGC11-silenced plants displayed significant downregulation of antioxidant enzyme genes (HcSOD, HcPOD, HcCAT) as well as stress-responsive genes (HcP5CS, HcLTP, HcNCED). Conversely, Arabidopsis lines overexpressing HcCNGC11 exhibited 20-47% higher antioxidant enzyme activities, increased osmoregulatory substances, enhanced chlorophyll content, and markedly reduced ROS accumulation compared to WT under salt stress. Molecular analysis of these transgenic lines showed upregulated expression of antioxidant genes (AtSOD1, AtPOD1, AtCAT1) and stress-responsive genes (AtSOS1, AtNHX1, AtCOR15). Protein-protein interaction studies, employing both yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays, identified multiple HcCNGC11 binding partners, including HcCaM7, HcCNGC21, HcTHI1, and HcTCP14. Collectively, these results demonstrate that HcCNGC11 positively regulates plant salt tolerance through modulation of antioxidant systems and stress-responsive pathways.

Glioblastoma is a highly aggressive primary brain tumour marked by extensive genomic and epigenomic alterations, cellular heterogeneity, and therapeutic resistance. Despite maximal surgical resection followed by chemoradiotherapy, median survival remains approximately 15 months, reflecting the tumour's invasive behaviour and adaptability. Advances in molecular oncology have revealed two promising therapeutic directions: epigenetic reprogramming and neurogenetic modulation. Glioblastoma exhibits widespread epigenetic dysregulation that disrupts transcriptional control, enhances cellular plasticity, and drives tumour progression. Concurrently, glioma cells aberrantly reactivate developmental programmes, acquiring neural stem cell-like states governed by transcription factors and signalling networks such as SOX2, OLIG2, Notch, and Wnt. These pathways collectively sustain stemness, lineage mimicry, and therapy resistance. This review proposes a focused conceptual framework centred on epigenetic and neurogenetic modulation as two core regulatory layers shaping glioblastoma plasticity and adaptive resistance. We highlight how DNA methylation, histone modifications, and chromatin remodelling contribute to transcriptional dysregulation, and how neurodevelopmental signalling reinforces malignant plasticity. Emerging preclinical and clinical studies combining epigenetic inhibitors with differentiation- or reprogramming-based therapies are discussed. By uniting mechanistic insights from chromatin biology, neurodevelopment, and cancer therapeutics, this integrative conceptual framework offers a structured lens for targeting key vulnerabilities underlying glioblastoma plasticity. The integration of these complementary strategies offers potential to enhance therapeutic responsiveness and improve disease management in this devastating malignancy.

This study aims to bridge toxicological target prediction and bladder cancer transcriptomics by systematically identifying molecular signatures and pathways that converge between PFOA-associated toxicological effects and bladder cancer biology, using an integrative multi-cohort computational framework.

Growing evidence indicates that nanoplastics (NPs), particularly polystyrene nanoparticles (PS-NPs), cross the blood-brain barrier and reach the hippocampus, where they induce neurotoxicity through oxidative stress, neuroinflammation, and synaptic damage. In the present study, we demonstrate that PS-NPs downregulate RNF139 in microglia, impairing the degradation of SCAP. Elevated SCAP levels trigger SREBP activation, disordered lipid metabolism, and enhanced lipid synthesis. Subsequently, mitochondrial dynamics are dysregulated, characterized by elevated mitochondrial reactive oxygen species, a drop in membrane potential, and diminished ATP synthesis. Under these pathological conditions, microglia become abnormally activated and secrete inflammatory factors such as TNF-α, IL-1β, and IL-6. This neuroinflammatory cascade induces neuronal damage and apoptosis, resulting in spatial cognitive impairment. Thus, our findings reveal a link between PS-NPs exposure, changes in microglial lipid metabolism, and nerve damage. They also identify targets for treating NP-induced neurological disorders.

SR12813 is an experimental cholesterol-lowering drug that reduces intracellular cholesterol through accelerated proteasomal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and is also recognized as a prototypical activator of the pregnane X receptor (PXR, NR1I2). Rifampicin, a clinically used antibiotic, likewise functions as a human PXR agonist. Although PXR-mediated induction of drug metabolism genes has been extensively characterized in hepatocytes and humanized mouse liver, comparatively little is known about the transcriptional effects of these ligands in intestinal and colon cancer cells. Here, we used RNA-sequencing in LS180 colon adenocarcinoma cells to compare transcriptional responses elicited by SR12813 and rifampicin. Both compounds induced canonical PXR targets, including CYP3A4, UGT1A1, and MDR1 (P-glycoprotein), whereas SR12813 preferentially upregulated genes associated with ketone body metabolism, lipid storage, and glycolysis. Complementary nuclear receptor reporter assays demonstrated that, in addition to robust PXR activation, SR12813 also functions as a partial agonist of peroxisome proliferator-activated receptor gamma, a receptor with critical roles in lipid metabolism and colon cancer biology. These findings demonstrate that SR12813 elicits overlapping, yet distinct transcriptional profiles relative to rifampicin, extending beyond xenobiotic metabolism to include metabolic pathways relevant to tumor progression. Collectively, our results highlight SR12813 as a dual-acting modulator of PXR and peroxisome proliferator-activated receptor gamma, and underscore its utility as a pharmacological tool for investigating nuclear receptor crosstalk in intestinal models. SIGNIFICANCE STATEMENT: SR12813 activates both pregnane X receptor and peroxisome proliferator-activated receptor gamma, demonstrating dual nuclear receptor modulation in colon cancer cells. By linking xenobiotic metabolism with lipid and mitochondrial pathways, this work uncovers previously unreported receptor crosstalk and provides a mechanistic framework for how diverse ligands can differentially shape transcriptional programs relevant to drug metabolism and tumor biology.

Metabolic control of chromatin and gene expression is emerging as a key mechanism influencing critical neuronal functions. Here, we found that the intermediary metabolite acetate enhanced long-term memory in female mice, which was associated with epigenetic and transcriptional remodeling in the dorsal hippocampus. Acetate-enhanced memory was driven by increased acetylation of the histone variant H2A.Z and increased expression of genes implicated in learning in the female dorsal hippocampus. The effect of acetate on dorsal hippocampal histone modifications and gene expression differed markedly between the sexes during critical windows of memory consolidation and recall, and home cage exposure to acetate without the learning and recall tasks did not recapitulate these effects. These findings elucidate the ways in which acetate exposure enhances memory.