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Results for “pathway rewiring”

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PubMed2026

Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.

BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC = 0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.

Benzamides↗

PubMed2026

Identification and characterization of non-canonical azole antifungal resistance pathways in Aspergillus fumigatus.

UNLABELLED: Human fungal infections, especially those caused by Aspergillus fumigatus, pose a significant global health threat, particularly in immunocompromised individuals. Azole antifungals are the primary treatment for this pathogen; however, the prevalence of azole-resistant A. fumigatus strains is steadily increasing. Mutations in cyp51A, which encodes an enzyme involved in ergosterol biosynthesis and the molecular target of the azoles, are well established to confer resistance in this fungal species. However, additional mechanisms governing resistance to this antifungal class remain understudied and poorly characterized, despite growing recognition of their importance in clinical resistance. In this study, we investigated the genetic basis of azole resistance in A. fumigatus isolates from clinical settings worldwide, with a particular focus on mechanisms independent of cyp51A (non-canonical). Using a combination of genomic and functional approaches, including whole-genome sequencing and transcriptomic analysis, we identified novel genetic variants and characterized population structure, advancing our understanding of the genetic diversity and evolutionary dynamics of resistance in A. fumigatus. By expanding our understanding of the complex genetic and molecular factors underlying azole resistance in this important human fungal pathogen, this research is poised to inform the development of novel antifungal strategies and contribute to global efforts to combat fungal infections. IMPORTANCE: Azole antifungals are the frontline therapy for infections caused by the opportunistic mold Aspergillus fumigatus, yet resistance to these drugs is rapidly increasing worldwide. Most studies have focused on mutations in cyp51A, the canonical target of azoles; however, a growing proportion of resistant clinical isolates lack these mutations, indicating that alternative resistance mechanisms are emerging. Here, we integrate population genomics, transcriptomics, and functional analyses across a global collection of isolates to define the architecture of cyp51-independent (non-canonical) azole resistance. We show that this resistance phenotype is strongly associated with a distinct population lineage and is driven by a highly polygenic network of metabolic, mitochondrial, and regulatory adaptations rather than single target site mutations. These isolates exhibit extensive transcriptional rewiring and metabolic remodeling under azole stress, suggesting distinct survival strategies beyond canonical resistance. Our findings reveal that azole resistance in A. fumigatus can evolve through diverse evolutionary routes and emphasize the need to monitor and therapeutically target non-canonical pathways that may increasingly contribute to antifungal treatment failure.

Aspergillus fumigatus↗

PubMed2026

Long-term functional synaptic integration of genome-edited retinal organoids in a primate model of macular degeneration.

Retinal organoids represent a promising regenerative strategy for restoring vision in retinal degenerative diseases, but the capacity of host cone bipolar cells in the primate macula to rewire with transplanted photoreceptors has not been established. In this study, we transplanted genome-edited ISL1-/- human retinal organoids lacking ON-bipolar cells into an acute laser-induced macular photoreceptor ablation non-human primate model. Using immunohistochemistry, ultrastructural imaging, and focal macular electroretinography, we demonstrate that host rod and cone bipolar cells actively extend dendrites toward grafted photoreceptors and form synaptic contacts, with evidence of functional signal transmission in a subset of transplanted eyes. Longitudinal, per-eye analyses revealed that host ON-bipolar responses improved in two of four eyes with ISL1-/- graft by up to 21.6% and remained stable for up to 2 years post transplantation. Moreover, OFF-pathway connectivity showed potential progressive maturation, with delayed increase in d-wave after 13 months in one of those eyes. These findings provide the first demonstration of long-term anatomical host-graft synaptic integration in the primate macula, establishing that central cone bipolar circuits retain the capacity for durable rewiring with human stem-cell-derived grafts. Our results highlight ISL1-/- retinal organoids as a promising approach for central vision restoration in macular degeneration.

Animals↗

PubMed2026

Functional and Proteomic Profiles of CD3(+) Plasma-Derived Small Extracellular Vesicles Differentiate Cancer Patients From Healthy Donors.

Small extracellular vesicles (sEV) released by T cells play a key role in immune regulation. Immune capture with anti-CD3 antibodies was used to isolate and study T cell-derived CD3(+)sEV from the plasma of patients with melanoma (MPs) or healthy donors (HDs). Functional responses induced in recipient target cells by CD3(+)sEV of MPs differed from responses induced by CD3(+)sEV of HDs. Approximating functions mediated by melanoma cell-derived sEV (MTEX), CD3(+)sEV of MPs reduced metabolic activity and proliferation of T cells while promoting activity in Mel526 cell targets. Proteomics profiling confirmed functional differences between CD3(+)sEV of MPs and HDs. Of 294 sEV-specific proteins identified in CD3(+)sEV, 226 were detected in the parent T cell proteome, confirming that the CD3(+)sEV proteome mimics that of the parent T lymphocytes. Among them were 66 differentially expressed proteins (DEPs) that differentiated vesicles from MPs and HDs. These DEPs were associated with processes linked to cancer-related functions. DEPs upregulated in CD3(+)sEV of MPs were associated with RHO-GTPase, cytokine, and MAPK signaling pathways. Thus, T cells of MPs were reprogrammed by MTEX to produce CD3(+)sEV that functionally resembled MTEX, partly recapitulated features of the tumor proteome, and differed from CD3(+)sEV of HDs. In cancer, the TEX-rewired T cells produce CD3(+)sEV that potentially could serve as a liquid biopsy of patients' T cells.

Humans↗

PubMed2026

Metabolomics Reveals Metabolic Characteristics of Functional Cure in Chronic Hepatitis B Treated With Entecavir Combined With Pegylated Interferon Alpha.

BACKGROUND: Entecavir (ETV) combined with pegylated interferon alpha (PEG-IFNα) improves chronic hepatitis B (CHB) functional cure rates, but therapeutic heterogeneity and underlying metabolic mechanisms remain unclear. This study used untargeted metabolomics to identify metabolic signatures, mechanisms, and predictive biomarkers of functional cure with ETV-PEG-IFNα. METHODS: Thirty-eight CHB patients were grouped into ETV monotherapy (Group E, n = 12) and ETV-PEG-IFNα combination therapy (Group Z, n = 26); Group Z was subdivided into cured (Group A, n = 13) and noncured (Group B, n = 13). Serum metabolomic profiling, multivariate statistics, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified differential metabolites. A random forest model was built using key metabolites. RESULTS: Three hundred eighty-eight metabolites were identified. Four differential metabolites distinguished Group A and B (upregulated guanidinoacetic acid, uracil 5-carboxylate; downregulated L-methionine S-oxide, oleamide), enriching amino acid metabolism pathways. Nine differential metabolites between Group E and Z implicated amino acid, immune, and fatty acid pathways. The random forest model based on the four Group A/B metabolites showed 88.5% cross-validation accuracy (AUC = 0.920), with L-methionine S-oxide and oleamide as key predictors. CONCLUSIONS: This study reveals metabolic rewiring in CHB functional cure via ETV-PEG-IFNα therapy, involving energy metabolism, oxidative stress, and immunomodulation, based on which we propose a tentative metabolism-immunity synergy model to guide future research. Key metabolites, especially L-methionine S-oxide and oleamide, show exploratory predictive potential for functional cure that warrants further validation in independent cohorts.

Humans↗

PubMed2026

Spatial niche remodeling of senescent liver-resident immune cells and its role in chronic liver diseases.

The liver serves the triple functions of metabolism, detoxification, and immune surveillance. Its unique immune microenvironment is shaped by continuous exposure to gut-derived antigens, pathogen-associated molecular patterns (PAMPs), and metabolites arriving via the portal vein, necessitating a delicate equilibrium between immune tolerance and effector activation. This equilibrium relies on the coordinated activities of diverse liver-resident immune cell populations-including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), dendritic cells (DCs), tissue-resident memory T cells (TRM), innate-like T cells, including mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδ T cells, innate lymphoid cells (ILCs, encompassing conventional NK cells and helper ILC subsets), and neutrophils. With advancing age and chronic injury, these resident immune cell populations undergo profound senescence-associated phenotypic reprogramming that is spatially organized along the portal-to-central axis of the hepatic lobule. Key mechanisms include: telomere dysfunction and DNA damage accumulation driving persistent activation of p53/p21 and p16/Rb pathways; mitochondrial dysfunction with mitochondrial DNA (mtDNA) leakage fueling the senescence-associated secretory phenotype (SASP) via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; epigenetic age acceleration, including genome-wide H3K27me3 heterochromatinization; and metabolic reprogramming toward glycolysis and lipid accumulation. This review proposes a "spatial niche remodeling" framework to integrate these cell-intrinsic senescence programs with their lobular context, intercellular communication network rewiring, and pathogenic roles across the spectrum of chronic liver disease-from steatosis through steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. We critically evaluate emerging senotherapeutic strategies targeting specific liver-resident immune cell subsets, discuss the barriers to clinical translation, and identify priority areas for future investigation, including the application of spatial multi-omics, humanized models, and epigenetic clock-guided clinical trials.

Kupffer cells↗

PubMed2026

Flux rewiring enables native D-glucosamine production in Escherichia coli.

D-Glucosamine is an industrially important amino sugar used in pharmaceuticals, nutraceuticals, and functional materials, yet its production remains dominated by chemical extraction from chitinous biomass, raising sustainability and allergen concerns. Escherichia coli natively synthesizes D-glucosamine directly from D-glucose through endogenous metabolism, revealing an underutilized amino sugar biosynthetic capability. Building on this native pathway, D-glucosamine production was enhanced through targeted genetic modifications and systematic optimization of nitrogen metabolism and cultivation conditions, reaching 9.2 g L-1 under shake-flask conditions. This work extends a phosphorylation-dephosphorylation strategy previously developed for neutral rare sugars to amino sugar biosynthesis, demonstrating the broader applicability of this metabolic design principle. Phosphatase identity emerged as a key control point for product formation: YbiV was the most effective phosphatase for selective D-glucosamine production, whereas alternative phosphatases redirected flux toward D-sedoheptulose. This enzyme-dependent flux partitioning further enabled tunable co-production of D-glucosamine and D-sedoheptulose. Native amino sugar biosynthesis in E. coli provides a controllable framework for producing chemically distinct sugars through endogenous metabolism and establishes a generalizable strategy for engineering amino sugar and other nitrogen-containing metabolite biosynthesis.

Escherichia coli↗

PubMed2026

A duplicated female pathway gene figla-like evolves as the male sex-determining gene in tilapia.

As the largest group of vertebrates, fish exhibit frequent turnover of sex-determining (SD) genes. Here, we assemble a chromosome-level YY red tilapia genome and identify figla-like (figlal) as the SD gene on tilapia linkage group (LG) 1. Integrative phylogenetic and genomic evidence suggests that figlal originated from a tilapia-specific duplication and transposition of the ancestral bHLH family gene figla from LG12 to LG1. Fluorescence in situ hybridization reveals expression divergence between figla and figlal, with figla expressed in female oocytes and figlal expressed in male gonadal somatic cells during early gonadal differentiation. The shift in expression after duplication might be driven by the insertion of cis-regulatory elements mediated by transposable elements. Knockout of figlal in XY fish results in male-to-female sex reversal as indicated by ovarian morphology, down-regulation of the male pathway gene dmrt1, and up-regulation of the female pathway gene cyp19a1a in the gonads. In contrast, overexpression of figlal in XX fish induces female-to-male sex reversal. These findings implicate figlal as an SD gene on tilapia LG1 and reveal the history of a unique evolutionary innovation in which a female oocyte gene evolved into a male SD gene via duplication, transposition, and cis-regulatory rewiring.

Animals↗

PubMed2025

Immunosuppressants Rewire the Gut Microbiome-Alloimmune Axis Through Time-Dependent and Tissue-Specific Mechanisms.

BACKGROUND: Lifelong immunosuppressive therapy is required to prevent allograft rejection in organ transplantation. Current immunosuppressants effectively suppress adaptive and innate immune responses, but their broad, antigen-non-specific effects often result in severe off-target complications. It remains a significant unmet medical need in transplant medicine. RESULTS: In this study we investigated immunosuppressant effects of four major immunosuppressant classes, including tacrolimus, prednisone, mycophenolate mofetil (MMF), and fingolimod (FTY), on the gut microbiome, metabolic pathways, lymphoid architecture and lymphocyte trafficking after up to 30-day chronic exposure. Despite their distinct mechanisms of action and not designed to target the gut, all immunosuppressive drugs induced profound and time-dependent alterations in both intestine gene expression and gut microbiome composition. Progressive alterations from moderate early, drug-specific changes to a strikingly convergent microbial dysbiosis, marked by significant expansion of pathobionts of Muribaculaceae, occurred across all drug classes. Concurrently, all drugs uniformly induced significant suppression of mucosal immunity including B cell, immunoglobulin, and antigen recognition. Time-dependent changes in lymph node (LN) reorganization and cellular composition were also observed, marked by a progressive shift toward pro-inflammatory phenotypes in gut-draining mesenteric LNs and a gradual loss of tolerogenic architecture in peripheral LNs. Drug-specific metabolic alterations and distinct phases of intestinal transcriptional responses were also characterized. Notably, MMF and FTY demonstrated the most robust immunomodulatory properties, and were able to suppress alloantigen-induced inflammation through mediating regulatory T cell distribution and LN remodeling. CONCLUSIONS: Together, these findings highlight the underappreciated complexity and temporal dynamics immunosuppressants effects, particularly their impact on the gut and compartmentalized regulation of alloimmune in lymphoid tissues. Understanding these relationships offers new opportunities for refining immunosuppressive strategies to reduce treatment-related off-target complications and improve long-term organ transplant outcomes.

gut dysbiosis↗

PubMed2026

Reframing early gastric carcinogenesis through lineage, niche, and evolution.

Early gastric cancer is still commonly conceptualized as the endpoint of a linear sequence from chronic gastritis to intestinal metaplasia, dysplasia, and invasion. Yet recent single-cell, spatial, genomic, and functional studies indicate that this model incompletely captures the biology of early gastric carcinogenesis. Malignant potential is established progressively within a precancerous gastric field already shaped by somatic evolution, chronic inflammatory injury, and epithelial lineage distortion. Within this field, progression is concentrated in a restricted set of precursor states, particularly incomplete, hybrid, and stem-like metaplastic populations that display plasticity, persistence, and increasing compatibility with a supportive microenvironment. Fibroblast niche remodeling, immune protection loss, endothelial rewiring, genomic instability, epigenetic drift, and selective retention of advantageous molecular alterations further promote malignant commitment. In parallel, diffuse gastric cancer appears to follow a distinct route that may arise independently of conventional intestinal metaplasia through E-cadherin-deficient epithelial transformation and downstream chromatin reprogramming. Here, we synthesize recent evidence to propose an updated framework for early gastric carcinogenesis based on field evolution, lineage instability, ecosystem support, and pathway divergence. Rather than replacing the classical Correa cascade, this framework seeks to refine it by shifting the unit of risk assessment from histologic stage alone to biologically defined precursor states shaped by lineage instability, clonal persistence, niche permissiveness, and pathway-specific molecular constraints. This perspective shifts the emphasis of prevention from detecting smaller cancers to identifying and intercepting biologically committed precursor states before invasion occurs.

Humans↗

PubMed2026

FANCM is required for the PAX3::FOXO1-driven oncogenic program in rhabdomyosarcoma.

Many cancers are driven by mutationally altered transcription factors (TFs) that rewire cells to an oncogenic state. Cells must activate specific mechanisms to tolerate the burden of oncogenic TF activity. To define such mechanisms, we focused on a canonical oncogenic fusion protein-driven cancer, alveolar rhabdomyosarcoma (ARMS), where the PAX3::FOXO1 fusion protein hyperactivates and mislocalizes PAX3 and FOXO1 TF functions. Employing sequential functional genomic CRISPR-Cas9 screens, we identified FANCM, a DNA translocase in the Fanconi anemia pathway, as a selective dependency in PAX3::FOXO1+ ARMS. FANCM loss reduces fusion protein levels, induces myogenic differentiation, and disrupts the PAX3::FOXO1 transcriptional program, thereby halting oncogenic proliferation. Mechanistically, FANCM depletion exacerbates replication stress (RS) and DNA damage signaling, with chromatin-associated RS enriched at PAX3::FOXO1 target gene loci, resulting in selective downregulation of the oncogenic program. CRISPR exon-tiling screens prioritized FANCM's helicase and DNA-binding domains as essential for this dependency, linking FANCM-mediated replication fork binding to sustained oncogenesis.

ARMS↗

PubMed2025

De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.

Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.

Pyrimidines↗

PubMed2026

Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.

Prostate cancer progression is predominantly driven by androgen receptor (AR) signaling, and despite initial benefits of androgen deprivation therapy (ADT), most patients eventually develop lethal castration-resistant disease. Cyclic administration of supraphysiologic androgen (SPA) with ADT paradoxically suppresses tumor growth; however, responses are heterogeneous, and the mechanisms underlying the antitumor effects of SPA remain incompletely understood. In this issue of Cancer Research, Kumar and colleagues demonstrate that SPA induces a distinct metabolic response, characterized by AR-dependent induction of polyamine biosynthesis via ODC1 and AMD1. This metabolic rewiring elevates polyamine synthesis while concurrently depleting the methyl donor S-adenosylmethionine (SAM). Although increased polyamine metabolism by SPA may promote adaptive resistance, genetic or pharmacologic inhibition of ODC1 using difluoromethylornithine (DFMO) enhances SPA-induced growth suppression by disrupting protective polyamine pools and further exacerbating SAM depletion, revealing a metabolic vulnerability in SPA-treated prostate cancer cells. Supporting these findings, a clinical trial combining DFMO with bipolar androgen therapy (BAT) demonstrated reduced circulating polyamines in patients, confirming polyamine pathway suppression in patients with different genomic features. Together, this study uncovers a mechanistic link among androgen signaling, polyamine metabolism, and therapeutic response, providing a rationale for targeting metabolic dependencies to improve SPA efficacy. See related article by Kumar et al., p. 1148.

Male↗

PubMed2026

Integrative single-cell and genomic analysis reveals NMB as a driver of metastatic adaptation in esophageal squamous cell carcinoma via metabolic rewiring and immune evasion.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has high mortality, and metastasis is the leading cause of patient death. Neuromedin B (NMB) promotes tumor development in various cancers, yet its role in ESCC metastasis remains unclear. METHODS: We integrated single-cell transcriptomic data from matched primary and metastatic ESCC lesions (GSE309392) with bulk transcriptomic cohorts from TCGA and GSE53624. In silico gene perturbation, ligand-receptor communication analysis, and single-cell prognostic model construction were performed, followed by functional validation through siRNA-mediated NMB knockdown in TE-1 and KYSE30 cell lines. RESULTS: NMB was identified as a key gene enriched in metastatic ESCC lesions, and its high expression was associated with coordinated upregulation of oxidative phosphorylation pathway genes and aldo-keto reductase family antioxidant enzymes (AKR1C1, AKR1C2, AKR1B10). Genomic analysis revealed that NMB-high tumors carried a higher clonal mutation burden and a markedly increased frequency of NFE2L2 activating mutations (23% vs. 8%, P = 0.04). In silico knockout and correlation analysis identified AKR1C1 as a downstream effector of NMB. NMB expression was negatively correlated with CD8+ T cell and activated NK cell infiltration. CellChat analysis revealed communication between NMB-positive cells and monocytes via the TGM2-ADGRG1 axis, and specifically detected IFNG signaling. In the single-cell prognostic model, NMB-positive cells accounted for 50% of the high-risk group but only 20% of the low-risk group. TCGA-based survival analysis demonstrated that high NMB expression was associated with shorter overall survival (HR = 2.98, P = 0.03). In vitro NMB-targeted RNA interference markedly inhibited proliferation, colony formation, and migration in TE-1 and KYSE30 cells. CMap screening identified the endothelin-PDE5-cGMP axis as a potential therapeutic target. CONCLUSION: NMB serves as a key driver of metastatic adaptation in ESCC, conferring a survival advantage to tumor cells during metastatic colonization through genomic evolution and immune remodeling, with metabolic adaptation as a downstream consequence of genomic alterations.

NMB↗

PubMed2026

PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes.

BACKGROUND: PGM1-congenital disorder of glycosylation (PGM1-CDG) is frequently associated with cardiomyopathy. Although galactose therapy corrects glycosylation defects, cardiac dysfunction typically persists, suggesting a glycosylation-independent mechanism. Recent evidence of mitochondrial abnormalities in PGM1-deficient human and murine heart, together with the association of PGM1 with the Z-disk protein LDB3 (ZASP/Cypher), suggests a critical role for PGM1 in cardiomyocyte structural and energetic homeostasis. We hypothesized that PGM1-related cardiomyopathy arises from a glycosylation-independent disruption of Z-disk-mitochondrial coupling driven by loss of PGM1-LDB3 interactions, resulting in mitochondrial energy failure and impaired contractile function. METHODS: Induced pluripotent stem cell-derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays. RESULTS: PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro. In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy. CONCLUSION: Our data suggests PGM1 is key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction.

Humans↗

PubMed2026

Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.

UNLABELLED: Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in patients with recurrent high-grade glioma treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAM), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the TME. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2-M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62, and autophagosome accumulation and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and damage-associated molecular patterns (DAMP), such as IL1β, HMGB1, and extracellular ATP. Coculturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and proinflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the antitumor therapeutic efficacy of OD-0J1. SIGNIFICANCE: Leveraging JAG1 antagonism in the context of oncolytic virotherapy rewires macrophage polarization within the tumor microenvironment, which has wide implications for sensitizing tumors to antibodies, senolytic agents, and BiTE therapies.

Humans↗

PubMed2026

Redox Rewiring in Nicotine-Driven Gastric Carcinogenesis: Uncovering ROS-Dependent Oncogenic Circuits.

SIGNIFICANCE: Nicotine from tobacco products, secondhand smoke, and emerging delivery systems remains a major but underappreciated driver of gastric carcinogenesis (GC). Although reactive oxygen species (ROS) have long been implicated in tumor biology, current models incompletely explain how chronic nicotine selectively reprograms gastric epithelial signaling. This review advances the concept of redox rewiring, whereby nicotine establishes a persistent oxidative state that orchestrates multiple oncogenic programs via spatially compartmentalized NOX signaling. RECENT ADVANCES: We synthesize evidence for a unified model wherein nicotine activates nAChR/β-AR signaling, Ca2+ influx, PKC, and compartmentalized NOX-derived ROS to generate distinct oncogenic outputs. Beyond the established NOX/ROS/NF-κB/MAPK-driven IL-8 and MMP-9 axes, we integrate emerging evidence into three interconnected modules governing EMT/metastasis (ABL1/STAT3/COX-2/periostin), survival/chemoresistance (ERK/GLI1/Bcl-2), and invasion/immune evasion (miR-21/PDCD4). Collectively, these circuits suggest that ROS function not merely as damaging byproducts but as spatially organized signaling mediators dictating tumor behavior. CRITICAL ISSUES: A major challenge is distinguishing established mechanisms from incompletely validated models. The three proposed axes are testable hypotheses requiring experimental validation. Most data derive from in vitro studies with nonphysiologic nicotine concentrations, and artifacts from nonspecific ROS probes are common. Compensatory pathway activation and multi-target effects of natural products remain underexplored. FUTURE DIRECTIONS: We outline a precision-redox oncology roadmap linking pathway-specific biomarkers, mechanistically matched natural products, and biomarker-enriched trials. Priorities include genetic validation of the three axes, time-resolved ROS imaging, and pulsed natural product regimens. By reframing nicotine-driven GC as adaptive redox network remodeling, this review provides a framework for prevention, stratification, and next-generation therapy. Antioxid. Redox Signal. 00, 000-000.

gastric cancer↗

PubMed2026

Rewiring Cellular Context as A Central Mechanism Governing Cancer Stem Cell Survival: Insights from ESC Comparisons.

Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance, yet their remarkable persistence remains poorly understood. While CSCs share stemness attributes with embryonic stem cells (ESCs), including self-renewal, transcriptional plasticity, and permissive chromatin, they exhibit a fundamentally divergent regulatory logic that prioritizes survival over developmental fidelity. ESCs maintain globally open chromatin that supports transcriptional hyperactivity but predisposes them to apoptosis under genotoxic stress, whereas CSCs maintain dynamically inducible, permissive chromatin at survival loci while repressing differentiation programs, enabling adaptive stress responses. We advance the hypothesis that CSC persistence emerges not from any single factor, but from the integrative rewiring of signaling cascades (Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT/mTOR), stress-responsive transcription factors (HIFs, NF-κB, STAT3), and core pluripotency networks (OCT4, SOX2, NANOG) within a survival-centric context, reinforced by dynamic chromatin remodeling, inducible super-enhancer landscapes, and microenvironmental cues (hypoxia, inflammation, matrix stiffness). Within this framework, the E2F family serves as a key contextual integrator: in ESCs, constitutive E2F activity triggers p53-mediated apoptosis upon DNA damage, preserving genomic integrity; in CSCs, deregulated E2F activity redirects transcription toward DNA repair, antioxidant defenses, and anti-apoptotic programs. This functional divergence underscores that phenotypic outcome is determined by the broader cellular and epigenetic landscape rather than any single factor. We conclude that CSC persistence is an emergent property of this integrated, survival-centric program, fundamentally distinct from the developmental imperative of ESCs. Effective therapeutic strategies must therefore move beyond targeting individual pathways to dismantle the interconnected regulatory networks that define the CSC survival context, offering a more robust approach to overcome therapy resistance and prevent tumor relapse.

Cancer Stem Cells (CSCs)↗