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Results for “Metabolic Reprogramming”

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PubMed2026

Acidic Stress Induces Proteomic Reprogramming and Virulence-Associated Adaptation in Paracoccidioides brasiliensis.

Paracoccidioidomycosis (PCM) is a neglected systemic mycosis whose etiologic agents must adapt to acidic host niches such as phagolysosomes. Here, we used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics to define the response of Paracoccidioides brasiliensis to acidic stress (pH 4.5) versus control pH (6.5) after 5 and 24 h. We identified and quantified 4374 proteins, including 327 and 722 differentially abundant proteins at 5 and 24 h, respectively, revealing time-dependent proteomic reprogramming. Enrichment analyses highlighted proteolysis, protein metabolism, organonitrogen metabolism, MAPK- and SNF1-like signaling, central carbon metabolism, tyrosine metabolism, and ergosterol biosynthesis as major acid-responsive processes. Complementary assays showed pH-dependent extracellular proteolytic activity, increased adhesion to A549 pulmonary epithelial cells, and dynamic ergosterol remodeling. The proteomic data further indicated increased abundance of moonlighting proteins linked to adhesion and metabolic enzymes associated with ATP generation and melanin precursor production. Together, these findings indicate that P. brasiliensis adapts to acidic environments through coordinated regulation of proteostasis, metabolism, signaling, host-cell interaction, and membrane homeostasis, supporting survival and virulence potential in acidic host microenvironments.

Paracoccidioides↗

PubMed2026

Circadian reprogramming of inflammation and metabolism in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is driven by inflammation, fibrosis, and metabolic dysfunction. While circadian rhythm dysregulation is well documented in chronic disorders, its specific impact on CKD pathogenesis remains elusive. METHODS: We performed four-hour interval time-series RNA sequencing on renal tissues from control and CKD mice. We used the JTK_CYCLE algorithm to identify rhythmic genes and categorize them as lost, acquired, or sustained in CKD; we subsequently performed focused bioinformatic analyses. RESULTS: The renal circadian profile was substantially altered; acquired rhythmicity emerged as the dominant pattern, and core clock gene expression was disrupted. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that upregulated acquired-rhythmic genes in CKD were enriched in immune-inflammatory pathways; the expression of these genes peaked at Zeitgeber time (ZT) 12-16, consistent with a higher level of renal macrophage infiltration at ZT16 than at ZT0. Conversely, genes associated with nutrient and energy metabolism pathways were downregulated but acquired rhythmicity in CKD. Dapagliflozin improved renal function and restored the circadian expression rhythms of NR1D1 and p-BMAL1. CONCLUSIONS: CKD profoundly remodels the renal circadian transcriptome, driving immune-inflammatory and metabolic pathways into maladaptive rhythmicity. Furthermore, dapagliflozin can partially restore the expression of renal core clock genes.

Animals↗

PubMed2026

Lipid reprogramming of stratified squamous epithelium by the high-risk HPV E6 and E6/E7 oncoproteins.

INTRODUCTION: High risk human papillomavirus (HPV) infection and genome integration with pronounced expression of the viral E6/E7 oncogenes is the major cause of cervical cancer. Emerging evidence suggests that HPV reprograms host metabolism to support viral persistence and cellular transformation. However, global HPV oncogene-induced lipidomic reprogramming remains poorly understood, particularly at early stages of HPV-induced transformation. OBJECTIVE: We sought to define the regulation of lipid metabolism in squamous epithelia of transgenic mice expressing the HPV16 oncogene E6 alone or in conjunction with E7. METHODS: Untargeted lipidomics was used to identify novel lipid biomarkers in the skin and female reproductive tract (FRT) of HPV16 E6 and E6/E7 transgenic compared to wild-type (WT) mice. To investigate enzymatic dysregulation of lipids by HPV oncogene expression, we employed Lipid Network Explorer (LINEX2), which analyzes lipidomics data through lipid enrichment analysis. We also used the Global Natural Product Social Molecular Networking (GNPS) platform to enhance lipid identification, exploring molecular networking to improve feature annotation. RESULTS: Our lipidomic analysis produced several new observations. First, E6 expression caused a consistent alteration of glycerophospholipids, with particularly significant substrate-product shifts in the phosphatidylcholine (PC) to lysophosphatidylcholine (LPC) pathway in the skin. Second, E6/E7 expression caused a dysregulation of glucosylceramide (GlcCer) biosynthesis. Third, both E6/E7 expressing skin and FRT tissues exhibited a redox imbalance and increased levels of oxidized lipids, including oxylipins and several oxidized PCs. These findings suggest that HPV oncoproteins drive lipid reprogramming, potentially contributing to early HPV-related tumorigenesis. CONCLUSIONS: These findings provide new insights into HPV‑induced lipid reprogramming and establish a framework for future studies examining the functional and clinical relevance of lipid alterations in HPV‑associated cancers.

Animals↗

PubMed2026

Proteomic signatures of adipocyte recruitment in breast cancer.

The tumor microenvironment (TME) is increasingly recognized as a dynamic regulator of breast cancer progression, with adipocytes functioning as active contributors rather than passive bystanders. Here, we investigated the proteomic and morphologic reprogramming of breast cancer-associated adipocytes (BrCAAs) in response to triple-negative breast cancer (TNBC). Using conditioned medium from HCC1143 cells, we established an in vitro BrCAA model and performed mass spectrometry-based proteomics. Comparative profiling revealed 256 differentially expressed proteins, enriched for pathways including fatty acid degradation, carbon metabolism, and glycogen turnover, consistent with a metabolic shift from energy storage to energy supply. Gene ontology and protein-protein interaction analyses further identified cytoskeletal remodeling, adhesion dynamics, and secretory pathway activation, supporting BrCAA-driven microenvironmental remodeling. In the MMTV-PyMT mouse model, morphometric analysis demonstrated progressive size reduction and increased contour irregularity of adipocytes adjacent to tumors, correlating with proteomic evidence of metabolic stress. Importantly, BrCAAs localized at tumor interfaces were associated with increased microvessel density and CD105+ endothelial activation compared to desmoplastic zones. Proteomic enrichment highlighted pro-angiogenic remodeling, with validation of basigin (BSG), integrin αV (ITGAV), and 2,4-dienoyl-CoA reductase 1 (DECR1). Collectively, our findings establish BrCAAs as metabolically and structurally reprogrammed stromal components that promote tumor metabolism and localized angiogenesis, representing potential therapeutic targets in aggressive breast cancer.

Female↗

PubMed2025

Adipocyte-specific IGF1R knockout activates the β-catenin/apelin axis to combat diet-induced obesity in male mice.

AIMS: Obesity, driven by complex genetic and environmental interactions, remains a global health crisis with limited therapeutic options. The insulin-like growth factor 1 receptor (IGF1R) plays dual roles in metabolism and growth, but its tissue-specific functions in adipose biology are controversial. This study investigates how adipose-specific IGF1R knockout impacts systemic metabolism under high-fat diet (HFD) stress and explores the underlying mechanisms. METHODS: Adipose-specific IGF1R knockout mice (AdIGF1RKO) were generated by crossing Igf1rfl/fl mice with Adipoq-Cre transgenics. Mice were fed a normal chow diet (NCD) or HFD for 20 weeks. Metabolic phenotyping included glucose/insulin tolerance tests, body composition analysis and serum profiling. RNA-seq, Western blot and quantitative real-time reverse transcriptase PCR were used to identify molecular pathways. In vitro studies with stromal vascular fraction (SVF) cells validated β-catenin/apelin interactions. RESULTS: AdIGF1RKO male mice exhibited reduced adipose mass under NCD and resisted HFD-induced obesity, showing attenuated hepatic lipid deposition and improved glucose metabolism. Mechanistically, IGF1R knockout enhanced INSR and Akt phosphorylation, driving GSK3β-β-catenin activation and apelin upregulation. Apelin activated AMPK, suppressing lipogenesis and enhancing fatty acid oxidation. Notably, β-catenin's role shifted from inhibiting adipogenesis in precursors to promoting metabolic adaptation in mature adipocytes. CONCLUSION: We unveil a β-catenin/apelin-driven endocrine axis that reprograms energy metabolism under obesogenic stress. Therapeutically, targeting adipose IGF1R or apelin signalling could combat obesity while avoiding systemic toxicity. Limitations include unresolved β-catenin/Apln transcriptional mechanisms, APJ function and tissue-specific AMPK effects. Our findings redefine IGF1R's metabolic role and propose novel strategies for obesity-related disorders.

Animals↗

PubMed2026

Decoding context-dependent sirtuin pharmacology in cancer: Metabolic-epigenetic switches and precision therapeutic targeting.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Humans↗

PubMed2026

The OsUVR8-OsNAC3-OsERF117 signaling module mediates metabolic acclimation and climate adaptation in rice.

Ultraviolet-B (UV-B; 280 to 315 nanometers) radiation increasingly threatens crop productivity, yet the genetic basis of plant adaptation remains poorly understood. We delineate a UV-B signaling module in rice that links photoreceptor activation to transcriptional reprogramming and metabolic acclimation. The AP2/ERF transcription factor OsERF117 acts as a central regulator, directly activating flavonoid and melatonin biosynthetic genes to drive photoprotective metabolite accumulation and enhance UV-B stress tolerance. Promoter variation in OsERF117 defines 10 haplotypes across 4093 rice accessions, with high-expression haplotypes enriched in high-UV-B regions and correlated with adaptive divergence. OsERF117 is transcriptionally activated by OsNAC3, with a cis-regulatory SNP at an OsNAC3-binding site modulating responsiveness and contributing to subspecies diversification. Genetic and biochemical evidence supports a model in which UV-B-activated OsUVR8 promotes OsNAC3 activity and antagonizes OsCOP1-mediated ubiquitination and degradation in rice. This OsUVR8-OsCOP1-OsNAC3-OsERF117 module reveals how UV-B perception drives regulatory and metabolic diversification, offering targets for breeding UV-B-resilient crops.

Oryza↗

PubMed2026

Turnip mosaic virus alters phosphorus metabolism and shoot-root allocation without resource competition.

Plant viruses affect production through symptom induction in host plants. These symptoms could partially arise from nutrient deprivation: The resource competition hypothesis posits that massive viral replication deprives hosts of essential nutrients, yet direct evidence for phosphorus (P) competition is lacking. Moreover, it is reported that biotic stresses can lead to alterations on P metabolism. Using a hydroponic system enabling separate analysis of shoots and roots in adult Arabidopsis thaliana plants, we investigated whether Turnip mosaic virus (TuMV) drawed significant P internal pools leading to P competition or altered P metabolism. TuMV genomic RNA represented < 0.3% of the P pool allocated to 18S rRNA, refuting the resource competition hypothesis. Instead, TuMV induced a marked shoot-to-root P redistribution: Shoot/Root Pi and Porg changed from 1.7 to 1.04 to 0.71 and 0.68, respectively. This altered partitioning correlated with organ-specific gene expression changes: high-affinity transporters PHT1; 4 and PHT1; 5 were co-induced in shoots, whereas immunity-related PHT1; 4 was uniquely repressed in roots. The senescence-associated gene SEN1 showed opposite regulation between organs (repressed in shoots, induced in roots), distinguishing virus-induced responses from canonical senescence. Multivariate analysis revealed that shoots and roots only partially share physiological and molecular responses to TuMV. The virus reprograms phosphorus metabolism through organ-specific changes, not through resource depletion, and roots act as a distinct hub integrating infection response, senescence, and nutrient dynamics. This study advances the understanding of growth-defense trade-offs in plant mineral nutrition and identifies new targets for maintaining crop productivity under biotic stress.

Arabidopsis↗

PubMed2026

Sea urchin co-culture boosts abalone growth by reducing environmental stress and remodeling gut microbiota.

Biofouling and microenvironmental deterioration are major bottlenecks restricting the intensive aquaculture of Pacific abalone (Haliotis discus hannai). While co-culturing offers an eco-friendly mitigation strategy, the underlying mechanisms promoting abalone growth remain poorly understood. This study evaluated the growth performance of H. d. hannai co-cultured with varying densities of the sea urchin (Strongylocentrotus intermedius). By employing transcriptome and 16S rRNA sequencing of the abalone gut, we investigated the synergistic responses of host gene expression and gut microbiota. Compared with the monoculture group, the co-culture groups showed significantly less biofouling and greater growth of abalone, with the co-culture (n = 15) exhibiting the best outcomes. Transcriptomic analysis revealed 1444, 760, and 508 DEGs in G5, G10, and G15, respectively, compared with G0. These DEGs were significantly enriched in metabolic pathways, including glycolysis and sterol metabolism, indicating a shift in intestinal energy metabolism from stress defense toward growth under co-culture conditions. Gut microbiota profiling identified Proteobacteria and Firmicutes as the dominant phyla, with specific functional taxa (e.g., Psychrilyobacter and Akkermansia) enriched in a density-dependent manner. Furthermore, correlation analysis demonstrated that growth traits positively correlated with growth-promoting taxa (e.g., the unclassified AB1 lineage), but negatively correlated with potentially opportunistic taxa (e.g., Tabrizicola). These findings provide insights into a potential synergistic mechanism of "environmental stress alleviation-metabolic reprogramming-microecological remodeling" driving abalone growth, providing a theoretical foundation for optimizing co-culture systems and developing growth-associated biomarkers.

Animals↗

PubMed2025

Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency.

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced metabolic fitness, increased secretion of proinflammatory cytokines, and expansion of cytotoxic NK cell subsets. Through high-content genome-wide CRISPR screening in NK cells, this study reveals critical regulators of NK cell function and provides a valuable resource for engineering next-generation NK cell therapies with improved efficacy against cancer.

Humans↗

PubMed2026

Glucose-6-phosphate dehydrogenase variants modify 3D genomic organization to suppress maladaptive gene expression and vascular disease.

The 3D genome architecture is a higher-order organization of chromosomes within the nucleus that is critical to the control of epigenomic modifications. However, our knowledge regarding the role of 3D genomic organization in the regulation of vascular gene expression and function is lacking. In the present study, CRISPR-engineered rats modelled after two common polymorphisms (S188F and N126D) in human glucose-6-phosphate dehydrogenase (G6PD) revealed modifications to the 3D genome in aortas from rats expressing a deficient G6PD variant (S188F), but not a non-deficient one (N126D), is associated with: 1] up-regulated expression of TET enzymes that augmented expression of genes encoding antiproliferative proteins, 2] suppressed expression of genes encoding inflammatory/thrombotic/fibrotic proteins, and 3] reduced angiotensin II-induced aortic stiffness and hypertension. G6PD interacted with MATRIN-3, a nuclear matrix/scaffold protein, and a deficient G6PD variant increased the relative abundance of MATR3 and CCCTC-binding factors, potentially modifying 3D-genome structure. Additionally, G6PD deficiency-induced enrichment of H3K27ac likely influences the establishment and maintenance of the 3D genome. Therefore, we propose that the nexus between metabolism and the 3D genome regulates arterial gene expression and vascular disease.

Animals↗

PubMed2024

The Protective Role of DDIT4 in Helicobacter pylori-induced Gastric Metaplasia Through Metabolic Regulation of Ferroptosis.

BACKGROUND & AIMS: Helicobacter pylori (H pylori) infection is a significant factor leading to gastric atrophy, metaplasia and cancer development. Here, we investigated the role of the stress response gene DDIT4 in the pathogenesis of H pylori infection. METHODS: Cell lines, transgenic mice, and human tissue samples were implemented. Proteomics were performed on Ddit4+/+ and Ddit4-/- mice infected with H pylori strain PMSS1. C57BL/6 mice were administered with tamoxifen to induce gastric metaplasia. Stomach tissues were analyzed for histopathologic features, reactive oxygen species, Fe2+, lipid peroxidation, expression of DDIT4, and ferroptosis-related proteins. RESULTS: DDIT4 expression was upregulated at 6 hours but significantly decreased at 24 hours in response to H pylori infection in gastric epithelial cells. Gastric DDIT4 were downregulated in INS-GAS mice at 4 months post H pylori infection. Notably, H pylori infection led to more severe gastric metaplasia lesion in Ddit4-knockout mice. The proteomic profiling revealed an increase in ferroptosis in the gastric tissues of infected Ddit4-deficient mice, compared with infected wild-type mice. Mechanistically, knockout of DDIT4 promoted H pylori-induced ferroptosis through the accumulation of lipid peroxides and ROS levels, and alterations in proteins such as GPX4, ALOX15, and HMOX1. Overexpression of DDIT4 counteracted H pylori-induced stem cell marker CD44V9 through modulation of ferroptosis. Similarly, in another mouse model of gastric metaplasia treated with tamoxifen, as well as in human GIM tissues, we observed the loss of DDIT4 and induction of ferroptosis. CONCLUSIONS: Our results indicate that DDIT4 serves as a protective factor against H pylori-induced gastric metaplasia by metabolic resistance to ferroptosis.

Ferroptosis↗

PubMed2026

Enhancer and metabolic rewiring by KMT2C-COMPASS or KMT2D-COMPASS family loss in cancer creates druggable vulnerabilities.

Many epigenetic regulatory factors are targets of the somatic mutations found in patient tumours. Amongst the family of epigenetic regulatory complexes known as Complex of Proteins Associated with Set1 (COMPASS), the enhancer regulators histone-lysine N-methyltransferase 2C (KMT2C)-COMPASS and KMT2D-COMPASS are particularly critical for differentiation and cell fate specification. Their catalytic subunits, including the histone H3 lysine 4 (H3K4) monomethyltransferases KMT2C (also known as MLL3) and KMT2D (also known as MLL4) and the H3K27-specific demethylase lysine-specific demethylase 6A (KDM6A; also known as UTX), are encoded by some of the most frequently mutated genes across human cancers, particularly epithelial cancers. The multifaceted roles of KMT2C-COMPASS and KMT2D-COMPASS, the variety of KMT2C, KMT2D and KDM6A mutations found across all cancer types, and the tissue-specific impacts of compromised enhancer regulatory function have posed challenges for direct therapeutic targeting. However, KMT2C-COMPASS and KMT2D-COMPASS mutations also create tumour-specific and potentially targetable vulnerabilities. In this Review, we discuss the functional roles of KMT2C-COMPASS and KMT2D-COMPASS and the impact of their mutations on cancer progression. We outline potential therapeutic strategies to exploit vulnerabilities in cancer cells with altered KMT2C-COMPASS or KMT2D-COMPASS activity, including aberrant epigenetic regulatory complex activity, metabolic rewiring, defects in cell-cycle control and DNA repair, and increased immunogenicity.

Humans↗

PubMed2026

Impact of pH and Mycoplasma hominis endosymbiosis on Trichomonas vaginalis pathogenesis.

The parasite Trichomonas vaginalis colonizes the human vaginal tract and adheres to and lyses epithelial cells causing an inflammatory infection. The vaginal tract is typically acidic, ranging from pH 3.8 to 5.1; however, pathogenesis studies have previously been conducted on parasites grown at pH 5.9 to 6.2. Here we compared the adherence and cytotoxicity of T. vaginalis grown at pH 5.1 and pH 5.9, identifying changes in the surface proteome that contribute to increased pathogenesis of the parasite at pH 5.1. We show that growth of the parasite at pH 5.1 significantly enhances adherence to and lysis of host cells and that this is strongly amplified by the presence of a common bacterial endosymbiont, Mycoplasma hominis. Quantitative proteomics revealed the upregulation of putative surface proteins, three of which were found to be involved in increased parasite adherence and host cell killing. Mechanistic assays demonstrated that a Ricin B-like protein mediates parasite adherence dependent on host glycosaminoglycans via its carbohydrate-recognition domain, while an EF-hand-like protein is shown to promote Ca2+dependent adherence. Ricin B overexpression was found to reprogram host metabolism, activating ERK1/2 and HIF-1α and driving a Warburg-like glycolytic shift with greatly increased lactate release, which may create a nutrient-rich niche that supports parasite persistence and host cell cytotoxicity. These studies demonstrate a coordinated upregulation of multiple adhesins rather than a single factor at pH 5.1 in the presence of M. hominis and explore the mechanisms underlying the interaction of parasite surface proteins with the host cell.

Trichomonas vaginalis↗

PubMed2026

Molecular Regulation of Primordial Germ Cell Specification and Implications for In Vitro Gametogenesis.

Primordial germ cells (PGCs) are the embryonic precursors of gametes, essential for transmitting genetic and epigenetic information across generations. However, PGC specification occurs within a narrow developmental window and involves only a small number of cells, making it difficult to study in vivo. In vitro models using pluripotent stem cells have enabled the generation of primordial germ cell-like cells, but these systems often rely on exogenous signaling and exhibit variability in efficiency and epigenetic fidelity. In this review, we synthesize current understanding of PGC specification in mouse and human systems, emphasizing the integration of signaling pathways, transcriptional networks, epigenetic reprogramming, and metabolic regulation. Canonical regulators, including PRDM1, PRDM14, TFAP2C, and SOX17, function within a broader, interconnected network that establishes for PGC competence. Understanding these interactions will be crucial for advancing in vitro gametogenesis and improving mammalian reproduction.

mammalian reproduction↗

PubMed2026

Analysis and validation of abnormal signaling pathways and immune cell infiltration characteristics in digestive system cancers based on peroxisome-related genes.

BACKGROUND: Although emerging evidence suggests a role for peroxisomes in tumorigenesis, their functions in digestive cancers remain unclear. This study aims to investigate the association between peroxisomes and digestive tract tumors. METHODS: To systematically investigate peroxisomal functions in digestive cancers, we first constructed and validated tumor-specific prognostic signatures based on peroxisome-related genes (PRGs) through univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses. We then characterized the tumor immune microenvironment (TIME) with CIBERSORT, X-CELL, and EPIC algorithms, and identified tumor-specific and common signalings via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Focusing on hepatocellular carcinoma (HCC), we experimentally validated peroxisome-related therapeutic responses by profiling signature genes in radioresistant cells and an orthotopic transarterial chemoembolization (TACE) rat model. PEX13 knockdown further assessed peroxisomal role in radiosensitivity and targeted therapy response. Clinical relevance of PEX13 was evaluated in HCC cohort. Single-cell RNA sequencing dataset and lipidomics further revealed peroxisomal mechanisms in HCC progression. Finally, peroxisomal function in colorectal cancer (CRC) was validated in vitro. RESULTS: Novel peroxisome-related prognostic signatures demonstrated strong predictive power in HCC, colon adenocarcinoma, rectal adenocarcinoma, pancreatic adenocarcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, and cholangiocarcinoma. High-risk patients displayed an immunosuppressive microenvironment, characterized by increased infiltration of regulatory T cells, M2 macrophages, Th2 cells, or cancer-associated fibroblasts, or Th1 cells' reduction. Peroxisomes engaged in several distinct yet convergent pathways, most notably "positive regulation of response to stimuli". HCC prognostic genes were dynamically regulated in response to therapeutic stimuli, including radiotherapy, targeted therapy, and TACE. Clinically, the expression of PEX13 was markedly upregulated in tumor tissues from therapy-resistant HCC patients. Mechanistically, peroxisomal dysfunction induced by silencing PEX13 in HCC or UBE2D2 in CRC may overcome therapeutic resistance (radiotherapy/ lenvatinib resistance in HCC, radioresistance in CRC) through reprogramming lipid metabolism. CONCLUSIONS: Peroxisomes act as pivotal regulators of digestive cancer progression by modulating signaling pathways, the TIME, therapeutic resistance, and lipid metabolism. Targeting peroxisomal function, particularly in high-risk subgroups of HCC and CRC, warrants further exploration as a promising therapeutic strategy.

Peroxisomes↗

PubMed2025

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

Setdb2↗

PubMed2026

Monocarboxylate Transporter 2 (MCT2) Reduction Is Associated with Increased Lung Tumor Growth and Alterations in the Immune Microenvironment in a Subcutaneous Tumor Model.

Monocarboxylate transporter 2 (MCT2; SLC16A7) is a high-affinity pyruvate transporter implicated in cancer metabolism. However, its role in lung cancer progression and the tumor microenvironment remains unclear. This study examined the effects of MCT2 reduction on tumor growth and cell-type-specific transcriptional changes within the tumor microenvironment. MCT2 loxP/loxP mice were crossed with mCre-Tg mice, and MCT2 deletion was induced by tamoxifen. Control (CO) mice received vehicle treatment. TC1 cells (100,000 cells/mouse) were injected subcutaneously, and tumors were harvested after 24 days. Single-nucleus RNA sequencing (snRNA-seq) was performed on isolated tumor nuclei (4000 nuclei/sample; n = 3 per group) using the 10x Genomics Chromium platform. Data were processed with Cell Ranger v3.0.2 and Seurat v5.2.1, followed by differential expression and pathway enrichment analyses integrated with macrophage bulk RNA-seq data. Tumors in mice with systemic MCT2 reduction grew significantly faster than those in control mice, demonstrating an association between host MCT2 reduction and increased tumor growth. Transcriptomic analysis generated high-quality profiles from 6864 CO and 10,055 KO nuclei. Clustering identified 12 cellular populations and cell types. MCT2 reduction altered pathways involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid metabolism across multiple populations. Macrophages showed prominent transcriptional changes, including enrichment of MAPK, PI3K-Akt, IgSF-CAM, ECM, and cytokine-cytokine signaling pathways. These findings were supported by macrophage bulk RNA-seq data. Systemic MCT2 reduction was associated with increased tumor growth and broad transcriptional alterations within the tumor micro-environment. Differences in metabolic and immune-related transcriptional programs, particularly in macrophages, identify potential mechanisms associated with tumor progression that warrant further functional investigation.

Animals↗