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Results for “pathway perturbation”

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At least 19 recordsLinked to original sources
PubMed2020

Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer.

BACKGROUND: Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer METHODS: The genetic alterations of the CDK4/6 pathway in bladder cancer were first analyzed with The Cancer Genome Atlas database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anticancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD1 immunotherapy. RESULTS: Of the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 to 32 days compared to vehicle only controls (p = 0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI > 3) and in vivo, but palbociclib significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models. CONCLUSIONS: The CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.

Animals↗
PubMed2025

Multi-context modeling of driver pathways reveals common and specific mechanisms across 23 cancer types.

Discovery of cancer driver pathways is essential for targeted therapies, since these pathways govern tumor progression and treatment resistance. However, their context-specific patterns across populations remain poorly understood. Leveraging pan-cancer genomic data, we apply our two models, EntCDP and ModSDP, to perform stratified analyses from four perspectives: region, tumor type, age group, and risk factors. Our results reveal the regional biases in perturbed pathways, such as PI3K-Akt in Chinese patients and GPCR in American patients with bladder cancer. Subtype comparisons highlight the mTOR signaling in lung adenocarcinoma and the FoxO signaling in lung squamous cell carcinoma. Pediatric-adult comparisons emphasize the enrichment of Ras signaling in pediatric acute myeloid leukemia and PAK signaling in pediatric glioblastoma, respectively. Risk factor associations further link Notch-mediated pathways to alcohol consumption and CDKN-regulated pathways to obesity-related cancers. Our findings demonstrate the utility of stratified driver pathway analysis in uncovering common and specific mechanisms, which can help prioritize context-aware therapeutic targets.

Humans↗
PubMed2026

Untargeted metabolomics reveals differential metabolic pathways and biomarkers in the acute phase of Kawasaki disease.

INTRODUCTION: Kawasaki disease (KD) is one of the most common rheumatic diseases in children and manifests with multisystem clinical features. Using untargeted metabolomics, our study investigated alterations in small-molecule metabolites in plasma of children with acute KD. Our study aimed to identify differential metabolic pathways and potential biomarkers. METHODS: Plasma samples were collected from 30 children diagnosed with KD and 30 age-matched healthy controls (HC) at Jinhua Maternal and Child Health Hospital between January 2025 and December 2025. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to analyse plasma samples. Enriched pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and differential metabolic pathways were determined using MetaboAnalyst 5.0. Differential metabolites were screened using the nonparametric Mann-Whitney U-test and receiver operating characteristic curve area (AUC). The conservative average AUC from nested cross-validation was reported as the primary performance metric. Pearson correlation analysis was conducted to evaluate correlations between metabolites and clinical parameters. RESULTS: In total, 261 differential metabolites were identified between the KD and HC groups, including 87 lipids and lipid-like molecules, 69 organic heterocyclic compounds, 38 benzenoids, 34 organic acids, 14 phenylpropanoids, and 19 other compounds. Pathway analysis of these differential metabolites revealed 30 putatively enriched metabolic pathways for exploratory analysis. Of these pathways, primary bile acid biosynthesis, arginine biosynthesis, histidine metabolism, and phenylalanine-tyrosine-tryptophan biosynthesis were nominally associated with KD. Six metabolites with exploratory discriminatory performance (AUC > 0.8) were further identified: L-tyrosine, L-tryptophan, glutamine, histidine, histamine, and taurocholic acid. A combined model incorporating these metabolites achieved an apparent AUC of 0.984 in the full dataset; nested cross-validation yielded a more conservative AUC of 0.889 (95% CI 0.798-0.968), indicating promising exploratory discriminatory performance. CONCLUSION: Untargeted metabolomics enables identification of metabolically perturbed pathways during the acute phase of KD. L-tyrosine, L-tryptophan, glutamine, histidine, histamine, and taurocholic acid may serve as candidate biomarkers for acute phase of KD.

Kawasaki disease↗
PubMed2025

Enhancer remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.

The molecular mechanisms that drive essential patterning events in the mammalian embryo remain poorly understood. Analysis of transcription factor expression kinetics at peri-gastrulation stages of development suggest Otx2 as a candidate regulator of the definitive endoderm, the precursor of all gut-derived organs. Accordingly, timed OTX2 depletion in gastruloids or during directed differentiation results in abnormal definitive endoderm specification in mouse and human, characterized by altered expression of components and transcriptional targets of the canonical WNT signaling pathway, perturbed adhesion and migration programs, and de-repression of regulators of other lineages. These defects cumulate in impaired foregut formation. Mechanistically, OTX2 is required to activate a subset of endoderm-specific enhancers and to suppress select enhancers of other lineages, allowing timely exit from the primitive streak and correct specification of anterior endoderm. Our results establish OTX2 as an early gut regulator and suggest molecular principles underlying spatiotemporal cell identity conserved across germ layers and species.

Otx Transcription Factors↗
PubMed2025

UALCAN Mobile, an app for cancer proteogenomic data analysis.

Cancer is a complex disease affecting various organs and is a major cause of death worldwide. During cancer initiation, disease progression, and tumor metastasis, various genomic and proteomic alterations are observed. Recent technological advances have led to the generation of large amounts of molecular data, including genomics and transcriptomics. These large-scale datasets can be utilized to analyze and identify sub-class-specific cancer biomarkers and targets. However, there is a need for the development of user-friendly tools for large-scale data analysis, disseminating the analyzed data in a visualizable format to cancer researchers with no programming skills. We developed UALCAN, a comprehensive platform that allows users to integrate disparate data to better understand the genes, proteins, and pathways perturbed in cancer and make discoveries of potential biomarkers and targets. In the current study, we describe the development of the UALCAN Mobile application (app) that will provide cancer transcriptomic data obtained from The Cancer Genome Atlas (TCGA) project to evaluate protein-coding gene expression based on various stratifications, including stage, grade, race, gender, and molecular-subtypes across over 30 types of cancers. In addition, the UALCAN mobile provides data analysis options for epigenetic changes due to DNA promoter methylation and Clinical Proteomic Tumor Analysis Consortium (CPTAC) cancer proteomic data. The app provides access to large cancer molecular datasets on the go. To find changes in the expression of causative genes and proteins and to identify biomarkers and therapeutic targets, UALCAN mobile app will be extremely valuable. The "UALCAN Mobile" app is free to use and can be downloaded from both the iOS/Apple and the Android Play Store and has been downloaded over 100 times in each of iOS and android app stores.

app↗
PubMed2025

Multi-omic phenotyping of iPSC-derived neurons harboring the MAPT V337M mutation reveals tau hypophosphorylation and perturbed axon morphology pathways.

Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. This is in part due to an incomplete understanding of the normal functions of tau in development and aging, and how the associated molecular and cellular processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation or MAPT knockdown. RNA-seq and phosphoproteomics revealed that both V337M mutation and tau knockdown perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. Functional genomics screens uncovered regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau perturbs tau phosphorylation and axon morphology pathways that are relevant to the normal function of tau, which could contribute to previously reported cognitive changes in preclinical MAPT variant carriers.

Journal Article↗
PubMed1977

Purine and pyrimidine metabolism: pathways, pitfalls and perturbations.

The conceptual framework which underlies many studies of purine and pyrimidine metabolism in intact cells has been critically evaluated. The model that is implicit in many such studies is the single, partially purified enzyme. This paper gives examples both of instances in which the extrapolation of results of enzymes studies to intact cells has been successful and of instances in which enzymes behave differently in the intact cell than in cell extracts. Pitfalls in the extrapolation of results of enzyme studies to intact cells concern (a) metabolic pathways, (b) intracellular enzyme activities, (c) enzyme regulation, and (d) intracellular metabolite concentrations. Examples are also given of situations in which perturbations in one aspect of purine or pyrimidine metabolism lead to changes in other aspects, often distant in the network of reactions.

Adenine Phosphoribosyltransferase↗
PubMed2026

Attribution of PM2.5-Induced Transcriptomic Perturbation to Toxic Components.

Ambient fine particulate matter (PM2.5) is a chemically complex mixture whose health impacts are not fully captured by particle mass. Here, we developed an interpretable chemotranscriptomic framework to attribute PM2.5-induced molecular perturbations to toxicity-relevant components. PM2.5 collected from urban roadside and coastal environments was separated into whole, extractable, and unextractable fractions, characterized by LC/GC × GC-HRMS-based nontarget analysis and inductively coupled plasma mass spectrometry (ICP-MS), and evaluated using cytotoxicity testing and transcriptomic profiling in human bronchial epithelial cells. Urban PM2.5 exhibited greater cytotoxic potency per unit mass than coastal PM2.5, with extractable fractions accounting for most cytotoxic and pathway-level responses. Transcriptomics revealed distinct site-specific modes of action: urban PM2.5 preferentially induced oxidative stress, xenobiotic metabolism, and cell cycle suppression, consistent with acute, nonapoptotic injury, whereas coastal PM2.5 elicited weaker cytotoxicity but stronger interferon-mediated immune and apoptosis-related signaling. Integrating chemical abundance with pathway activity using random forest regression, SHAP interpretation, and mechanistic corroboration reduced 5,033 detected features to 444 pathway-linked candidate drivers. Fewer than 5% of features explained ∼95% of cumulative model contribution. Standard-confirmed contributors included plasticizer-related compounds, aromatic and heteroaromatic combustion products, and copper for urban PM2.5 and secondary/aged organics and nickel for coastal PM2.5. These findings support mechanism-informed prioritization of hazardous PM2.5 components beyond mass-based assessment.

Particulate Matter↗
PubMed2026

Genome-Wide Impact of Human DBR1 Depletion on RNA Processing Networks Reveal a Connection Between Pre-mRNA Splicing, mRNA Surveillance and Stress Granule Dynamics.

The RNA lariat debranching enzyme DBR1 is essential for intron turnover and RNA metabolism, yet its broader impact on transcriptome regulation remains incompletely defined. To elucidate the consequences of DBR1 depletion, we performed transcriptome-wide RNA sequencing of DBR1-knockdown and wild-type HEK293 cells. Differential expression analysis revealed widespread perturbations in pathways linked to RNA splicing, mRNA surveillance, translational control, and stress-granule biology. Many of the most significantly altered transcripts encode splicing factors and RNA quality-control components, underscoring DBR1's influence on post-transcriptional regulation. Alternative splicing analysis showed changes across multiple event types, with exon skipping accounting for >50% of events, followed by mutually exclusive exons, alternative 5' and 3' splice sites, and retained introns, indicating that DBR1 depletion induces pervasive splicing defects. Direct spliceosome inhibition using isoginkgetin (blocks tri-snRNP recruitment) and pladienolide B (targets SF3B1) reproduced the DBR1-KD mis-splicing patterns of cell signaling genes and factors involved in RNA metabolism, supporting a functional link between DBR1 activity and alternative splicing. Notably, DBR1 knockdown revealed a subset of transcripts that are both NMD-sensitive and enriched within stress granules. Consistent with this observation, G3BP1 immunopurification and confocal microscopy further support a role for DBR1 and UPF1 in stress-granule dynamics, suggesting that these factors may participate at distinct stages to influence mRNA fate under stress conditions. Together, these findings indicate that DBR1 functions beyond lariat RNA turnover as a common regulator of RNA processing, transcriptome stability, and stress granule homeostasis, revealing intricate crosstalk between RNA splicing and RNA quality control pathways in human cells.

Humans↗
PubMed2026

Chemogenomic maps reveal a PRDX1-dependent iron-damage axis in the DNA damage response.

The DNA damage response (DDR) is a sophisticated network of cellular pathways whose perturbation leads to genome instability and is a key hallmark of oncogenesis. Here, we present data from 32 genome-scale loss-of-function CRISPR interference chemical-genetic screens with inhibitors targeting core constituents of the DDR machinery (PARP, ATR, ATM, DNAPK and WEE1), as both single agents and in combination with poly(ADP-ribose) polymerase inhibitors. These experiments identify >1,000 genes whose perturbation modifies the DDR and provides a rich resource to the DDR community. In addition, this compendium of functional genomics data reveals key principles governing the DDR and highlights a strong chemical-genetic interaction between loss of activity of the peroxiredoxin PRDX1 and all tested DDR inhibitors through a mechanism involving iron availability mediated by an MRGBP-PAX7-IREB2 axis. Our data position PRDX1 as a key suppressor of DNA damage accumulation and potential druggable target in combination with DDR inhibitors.

Journal Article↗
PubMed2026

Multimodal analysis of CD38 in T-cell Acute Lymphoblastic Leukemia Identifies Combinatorial Therapeutic Strategies.

Outcomes for pediatric patients with refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) are poor, underscoring the need for improved therapeutic strategies. CD38, a type II transmembrane glycoprotein, is a promising target in T-ALL, with clinical trials evaluating CD38-targeting immunotherapies in frontline and relapsed settings. However, the biological role of CD38 in T-ALL has not been systematically defined. We interrogated CD38 biology through multimodal profiling of pediatric T-ALL samples. Bulk RNA sequencing of 1,335 primary tumors revealed that CD38 expression varies across genomic and immunophenotypic subtypes in T-ALL. Flow cytometry of 150 primary samples and CITE-sequencing of 40 cases demonstrated broad surface expression of CD38. A transcription factor CRISPR-screen identified RUNX1, RUNX3, and TP53 as candidate positive regulators of CD38. Metabolomic profiling of cell lines further revealed disruption of the polyamine pathway following CD38 perturbation. Supporting this finding, co-targeting CD38 with difluoromethylornithine (DFMO), a polyamine metabolism disruptor, improved survival in preclinical models. Across transcriptomic datasets, including primary tumors, cell lines, and patient-derived xenograft models, IL32 expression consistently decreased following CD38 loss or negativity, supporting an association between CD38 and inflammatory signaling pathways. Additionally, CD38 and LCK expression were positively correlated across majority of genomic subtypes, implicating SRC kinase signaling. Consistent with this, daratumumab in cell lines increased LCK phosphorylation, and combination therapy with dasatinib improved survival compared to monotherapy. Collectively, these findings define previously unrecognized interactions between CD38 and targetable pathways and genes in T-ALL and identify rational combinatorial strategies to enhance CD38-directed therapies and reduce relapse risk.

Journal Article↗
PubMed2025

Genetic mapping and predictive modeling of paralog synthetic lethality.

Paralogs are abundant in the human genome and thought to be a primary source of synthetic lethality, yet the vast paralogome remains largely uncharacterized. A digenic screen of 36,648 paralogous pairs in the human genome revealed that synthetic lethalities were infrequent and varied in penetrance in different tumor backgrounds. We hypothesized that the variable penetrance of synthetic lethalities resulted from complex polygenic interactions with different cellular contexts. A machine learning classifier of a subset of paralog pairs tested across 49 cancer models revealed that endogenous perturbations in related pathways predicted paralog synthetic lethality. Further, predictive modeling of paralog synthetic lethality showed that the strength of synthetic lethal interactions was largely due to the overlap and essentiality of the protein-protein interaction networks shared by the paralog pairs. Collectively, this study tested 36,648 digenic paralog interactions and delineated the key feature classes that underlie the heterogeneity of paralog synthetic lethalities.

Humans↗
PubMed2026

UVB-aged polystyrene microplastics induce enhanced stress responses in human proximal tubular cells.

Microplastics (MPs) are increasingly detected in human biological matrices, raising concerns about their potential systemic effects, including on the kidney. However, the cellular responses of renal tubular epithelium to MPs and the role of environmental aging processes in modulating their biological activity remain poorly defined. Under environmental conditions, MPs undergo photo-oxidative transformations that alter their surface chemistry and may influence their interactions with biological systems. In this study, we investigated the effects of 1 µm polystyrene MPs in virgin (MPsV) and UVB-oxidised (MPsOx) forms in a human renal proximal tubular cell line (HK-2). Cells were exposed to MPs (25 and 50 µg/mL), and multiple endpoints related to cellular stress and genomic stability were evaluated, including lysosome-associated responses, oxidative damage, DNA integrity, micronucleus formation, DNA-content distribution profiles as an indirect proxy of proliferative status, and cytoskeletal organisation. Exposure to MPs induced measurable stress responses in tubular cells, with oxidised particles generally eliciting stronger effects than MPsV. These responses were consistent with increased oxidative stress, lysosome-associated cellular responses, genomic instability-associated alterations, activation of stress-responsive molecular pathways, and cytoskeletal perturbation. Collectively, these findings indicate that environmentally aged polystyrene MPs elicit more evident cellular stress responses than their virgin counterparts in HK-2 cells. Our results highlight the importance of incorporating environmentally transformed MPs into toxicological testing frameworks to improve the biological relevance of hazard assessment.

Genotoxicity↗
PubMed2026

Genomic and molecular landscape of early onset colorectal cancer: Emerging insights and clinical implications-A systematic review.

BACKGROUND: Early onset colorectal cancer, defined as colorectal malignancy occurring before age 50, has been rising globally. Increasing molecular evidence suggests that early onset colorectal cancer is not merely a premature form of late-onset colorectal cancer but a distinct biologic entity with unique genomic and transcriptomic profiles. METHODS: A systematic PubMed search using the terms "early onset colorectal cancer," "genomic," and "molecular" identified 270 records. Eighteen original studies met the inclusion criteria and were supplemented by references from selected articles. Extracted data encompassed clinicopathologic characteristics, genomic and epigenetic alterations, and dysregulated signaling pathways distinguishing early onset colorectal cancer from late-onset colorectal cancer. RESULTS: Evidence from approximately 19,888 patients with early onset colorectal cancer was synthesized across genomic, transcriptomic, and clinical data sets. Early onset colorectal cancer showed a predominance in distal and rectal sites, a slight male bias, and a higher prevalence among Hispanic and Asian populations. Compared with late-onset colorectal cancer, early onset colorectal cancer exhibited lower B-Raf proto-oncogene, serine/threonine kinase V600E mutation and CpG island methylator phenotype-high methylation frequencies but higher rates of tumor protein p53, Kirsten rat sarcoma viral oncogene homolog, and DNA-repair gene alterations. Distinct comutation patterns (F-box and WD repeat domain containing 7-neurogenic locus notch homolog protein 3-phosphoinositide-3-kinase regulatory subunit 1 and adenomatous polyposis coli-tumor protein p53) and overexpression of immediate-early response genes (Proto-Oncogene c-Fos, EGR1, DUSP1, and CYR61) defined its transcriptional landscape. Perturbations of Wingless/Integrated signaling pathway, mitogen-activated protein kinase, phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin, and DNA-repair pathways, along with global long interspersed nuclear element-1 hypomethylation, indicated heightened genomic instability. CONCLUSION: Early onset colorectal cancer develops through tumor protein p53-driven genomic instability and defective DNA repair rather than the canonical CpG island methylator phenotype-B-Raf proto-oncogene, serine/threonine kinase axis. Recognition of these molecular distinctions is essential for age-specific risk assessment, screening, and precision therapeutics. Further integrative studies are needed to elucidate environmental and genetic contributors and identify novel biomarkers and treatment targets.

Humans↗
PubMed2026

Penicillium melinii promotes root growth through subtle host reprogramming across model and crop species.

Root development is highly responsive to microbial interactions, yet the mechanisms by which beneficial fungi promote root growth remain incompletely understood. Here, we identified Penicillium melinii 'isolate 2' through a screen of endophytic fungi isolated from Arabidopsis and characterized it as a promoter of root development in both Arabidopsis and crop species. We combined phenotyping in vitro, rhizotron, greenhouse and field assays with reporter and mutant analyses, transcriptomics, phytohormone profiling and sequencing and annotation of the fungal genome to investigate the basis of this interaction. P. melinii consistently stimulated root growth and modified root architecture across experimental systems and host species. These effects were associated with subtle but reproducible host transcriptional reprogramming, supporting a model in which the fungus fine-tunes endogenous developmental programmes rather than broadly perturbing stress or growth pathways. Genetic and reporter analyses further suggested that this interaction modulates root branching through localized developmental reprogramming. Genomic analysis provided a framework for understanding the fungal traits associated with this beneficial interaction. The conservation of the response across model and crop species supports the relevance of P. melinii as both a useful experimental system to study beneficial plant-fungus interactions and a promising candidate for improving root traits and crop performance.

Penicillium melinii↗
PubMed2025

Longitudinal profiling of IDH-mutant astrocytomas reveals acquired RAS-MAPK pathway mutations associated with inferior survival.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant astrocytomas represent the most frequent primary intraparenchymal brain tumor in young adults, which typically arise as low-grade neoplasms that often progress and transform to higher grade despite current therapeutic approaches. However, the genetic alterations underlying high-grade transformation and disease progression of IDH-mutant astrocytomas remain inadequately defined. METHODS: Genomic profiling was performed on 205 IDH-mutant astrocytomas from 172 patients from both initial treatment-naive and recurrent post-treatment tumor specimens. Molecular findings were integrated with clinical outcomes and pathologic features to define the associations of novel genetic alterations in the RAS-MAPK signaling pathway. RESULTS: Likely oncogenic alterations within the RAS-MAPK mitogenic signaling pathway were identified in 13% of IDH-mutant astrocytomas, which involved the KRAS, NRAS, BRAF, NF1, SPRED1, and LZTR1 genes. These included focal amplifications and known activating mutations in oncogenic components (e.g. KRAS, BRAF), as well as deletions and truncating mutations in negative regulatory components (e.g. NF1, SPRED1). These RAS-MAPK pathway alterations were enriched in recurrent tumors and occurred nearly always in high-grade tumors, often co-occurring with CDKN2A homozygous deletion. Patients whose IDH-mutant astrocytomas harbored these oncogenic RAS-MAPK pathway alterations had inferior survival compared to those with RAS-MAPK wild-type tumors. CONCLUSIONS: These findings highlight novel genetic perturbations in the RAS-MAPK pathway as a likely mechanism contributing to the high-grade transformation and treatment resistance of IDH-mutant astrocytomas that may be a potential therapeutic target for affected patients and used for future risk stratification.

IDH1 mutation↗
PubMed2026

Functional perturbation reveals context-dependent contributions of nuclear receptors to drug-induced hepatic steatosis.

Drug-induced hepatic steatosis is mediated by diverse molecular mechanisms, yet several nuclear receptors have been proposed as molecular initiating events or early key events within adverse outcome pathways for hepatic steatosis. However, direct functional evidence supporting these mechanistic roles in human-relevant experimental systems remains limited. The present study evaluated the contribution of selected nuclear receptors to drug-induced hepatic steatosis using complementary human hepatic in vitro models. Stable short hairpin RNA-mediated knockdown of individual nuclear receptors was established in HepG2 and differentiated HepaRG cells, followed by exposure to representative steatogenic drugs, including valproic acid, amiodarone, tamoxifen, and rifampicin. In parallel, primary human hepatocyte spheroids were used to compare drug-induced lipid accumulation with direct pharmacological activation of individual nuclear receptor pathways. While depletion of multiple nuclear receptors markedly affected oleic acid-induced lipid accumulation, drug-induced steatogenic responses exhibited predominantly selective and compound-specific receptor dependencies. In differentiated HepaRG cells, nuclear receptor depletion influenced basal lipid homeostasis more strongly than valproic acid-induced lipid accumulation. Conversely, direct activation of liver X receptor and peroxisome proliferator-activated receptors α and γ in primary human hepatocyte spheroids induced robust lipid accumulation, whereas most steatogenic drugs produced comparatively modest responses. These findings demonstrate that the contribution of individual nuclear receptors to drug-induced hepatic steatosis is highly compound- and context-dependent and cannot be explained by a single conserved receptor pathway. This study provides functional evidence from complementary human-relevant hepatic models that supports refinement of hepatic steatosis adverse outcome pathways and highlights the value of targeted perturbation strategies for mechanistic toxicology.

Adverse outcome pathway, HepaRG↗
PubMed2026

3D Proteomics: Structural, Functional, Chemical and Biomarker Discovery Proteomics With LiP-MS.

Protein structural dynamics drive changes in protein function, making the capture of such dynamics essential for interrogating biological systems. Here we review limited proteolysis coupled to mass spectrometry (LiP-MS), a structural and chemical proteomics method that uses changes in susceptibility to protease cleavage to profile proteome-wide protein structural changes within complex biological samples. In the decade since its development, LiP-MS has become a broadly used structural proteomics method, with peptide-level resolution. It has identified drug targets, delineated altered cellular pathways in response to complex perturbations, revealed structural information on otherwise challenging protein targets, and demonstrated the new concept of structural biomarkers of disease. Because LiP-MS simultaneously probes numerous types of molecular events, such as molecular binding, changes in enzyme activity, chemical modifications, allosteric conformational changes, aggregation, and unfolding, it supports a new proteomics workflow which we term 3D proteomics. This workflow enables the detection of specific functional sites within proteins that are altered upon perturbation, thereby guiding the generation of molecular hypotheses. Further, by globally profiling structural in addition to protein abundance changes, LiP-MS has proven able to greatly increase the information content of functional proteomics screens. In sum, LiP-MS has supported the development of a novel conceptual framework for generating, visualizing, and interpreting structural proteomics data with peptide level resolution, thereby comprehensively probing biological systems. Here we survey the applications of LiP-MS, discuss methodological variants developed by us and others, and describe the use of this new type of omics readout for structural, functional, chemical, and biomarker discovery proteomics.

Proteomics↗