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PubMed2026

Transmitochondrial pigs reveal causal effects of mitochondrial DNA on backfat thickness via nuclear epigenetic reprogramming.

Mitochondrial DNA (mtDNA) polymorphisms have been associated with production traits in farm animals, including backfat thickness in pigs, yet direct in vivo evidence establishing a causal link between specific mtDNA haplotypes and fat deposition remains limited. In this study, we generated transmitochondrial pigs (mitopigs) by combining the Dapulian nuclear genome with Wuzhishan mtDNA via somatic cell nuclear transfer, introducing 23 mtDNA mutations relative to controls. Mitopigs exhibited significantly increased backfat thickness at 5 months, a difference that persisted in their offspring, without significant differences in body weight, body size, or litter size. Fibroblasts derived from mitopigs exhibited reduced mtDNA copy numbers, decreased expression of mitochondrial biogenesis genes (PPARA, PPARGC1A, RRM2B, and LRPPRC), impaired mitochondrial respiration, elevated reactive oxygen species (ROS), and upregulated adipogenic transcription factors (CEBPA, CEBPB, and PPARG). Consistent with these fibroblast findings, backfat tissue of mitopigs showed corresponding upregulation of adipogenic transcription factors and downregulation of mitochondrial biogenesis genes. Integrated transcriptomic and whole-genome bisulfite sequencing (WGBS) analyses revealed nuclear transcriptional reprogramming that was closely associated with differential DNA methylation, predominantly affecting mitochondrial function and lipid metabolism pathways. Mitopig fibroblasts also showed a pro-inflammatory response to lipopolysaccharide stimulation, with elevated expression of IL-12, NOS2, RELA, and TNF-α. Our findings provide direct in vivo evidence that mtDNA variants regulate adiposity in pigs through mitochondrial dysfunction, oxidative stress, and nuclear epigenetic modulation, highlighting the potential for incorporating mtDNA haplotype information into pig breeding programs as a complementary strategy to nuclear genomic selection.

Adipogenesis↗

PubMed2026

Integrated transcriptomic and metabolomic analysis reveals candidate regulatory networks associated with starch accumulation in tetraploid potato.

Potato (Solanum tuberosum L.) tuber starch is a major determinant of crop quality and industrial value, yet the regulatory mechanisms underlying starch accumulation in autotetraploid cultivars remain poorly resolved. Here, we performed integrated transcriptomic and metabolomic analyses using a segregating tetraploid population derived from parents with contrasting starch content. Extreme phenotypes were selected to systematically dissect the molecular basis of starch accumulation. Transcriptome profiling revealed extensive transcriptional reprogramming between high- and low-starch genotypes, with differentially expressed genes significantly enriched in carbohydrate metabolism, particularly the starch and sucrose metabolism pathway. Notably, multiple transcription factor families, including AP2/ERF, MYB, and bHLH, were prominently represented, suggesting coordinated regulatory control. Metabolomic analysis identified substantial metabolic divergence, with differentially accumulated metabolites predominantly enriched in starch and sucrose metabolism as well as secondary metabolic pathways. Most metabolites exhibited negative associations with starch content, indicating competitive carbon allocation between primary and secondary metabolism. Integrative multi-omics analysis further resolved a core regulatory module comprising key structural genes and transcription factors tightly associated with starch-related metabolites. In particular, genes involved in sucrose cleavage and ADP-glucose metabolism, together with trehalose-6-phosphate synthase (TPS) and UDP-glucose-associated pathways, emerged as critical nodes linking carbon flux to starch biosynthesis. Correlation network analysis suggested that AP2/ERF-, MYB-, and bHLH-type transcription factors modulate these pathways by coordinating structural gene expression and metabolic flux distribution. Collectively, our study establishes a transcriptional-metabolic framework for starch accumulation in tetraploid potato, highlighting the central role of carbon allocation and signaling intermediates in shaping starch content, and providing candidate targets for molecular breeding and genome editing.

Solanum tuberosum↗

PubMed2026

Mycobacterium tuberculosis MEM39 (Rv1977) hijacks host aldolase A (ALDOA) to subvert immunometabolism to facilitate bacterial intracellular survival.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the leading cause of infectious disease-related death. As a major intracellular pathogen, Mtb can escape clearance by the immune system, but the underlying molecular mechanisms remain incompletely elucidated. Specific genomic regions of deletion (RD)-encoded proteins in virulent Mtb H37Rv have been implicated in modulating pathogenicity and immunity. Here, we report a novel RD15-encoding protein, Rv1977 (a mycobacterial cell wall protein with a size of 39 kDa, named MEM39), which facilitates Mtb survival in macrophages. The survival of the Mtb H37Rv MEM39-deficient strain is reduced in both macrophage and murine infection models. Furthermore, the mycobacterial MEM39 protein binds fructose-diphosphate aldolase A (ALDOA), a key enzyme of glycolysis, thereby impairing ALDOA enzyme activity, disrupting macrophage metabolite flux, and reducing lactate production. The MEM39-ALDOA interaction also suppresses lysosomal acidification; reduces NLRP3 inflammasome activation and the production of proinflammatory cytokines (TNF-α, IL-6 and IL-1β); and thereby promotes bacterial survival within macrophages. Disruption of the interaction between MEM39-ALDOA and a cell-penetrating synthetic peptide (VLARYASICQ) significantly suppressed Mtb survival by restoring lactate production, lysosome acidification and proinflammatory cytokine production in both macrophage and mouse infection models. These findings revealed that mycobacterial MEM39 negatively regulates host immune defense through reprogramming ALDOA-mediated glycolysis in macrophages, thereby forming a "mycobacterial MEM39 virulence factor-glycolysis metabolism-immunity" regulatory axis. Targeting MEM39 or the MEM39-ALDOA interaction interface holds promise as a new therapeutic strategy against tuberculosis.

Mycobacterium tuberculosis↗

PubMed2026

A chromosome-level genome assembly and developmental transcriptome profiling reveal stage-specific remodeling of the molecular chaperone system in Helicoverpa armigera.

Helicoverpa armigera is one of the most destructive lepidopteran pests worldwide owing to its remarkable polyphagy, long-distance migration, and rapid adaptation to insecticides. Here, we present a chromosome-level genome assembly of H. armigera generated from a field-collected individual in southwestern China, providing a valuable resource for future population genomic and pangenome studies. Developmental transcriptome analyses of first-instar larvae, fifth-instar larvae, and adults identified 6817, 3519, and 5518 differentially expressed genes, respectively, including 797 shared among all developmental transitions. Functional enrichment and co-expression network analyses revealed extensive transcriptional reprogramming, characterized by coordinated regulation of glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation, indicating dynamic metabolic remodeling during development. Genome-wide analysis identified 77 heat shock protein (HSP) genes belonging to six subfamilies. These genes were unevenly distributed across chromosomes, with HSP20 members exhibiting extensive tandem duplication. Expression profiling revealed pronounced stage specificity, suggesting progressive remodeling of molecular chaperone networks during development. Early larvae primarily relied on HSP40/HSP60/HSP70 and HSP10/HSP60 chaperone systems; fifth-instar larvae exhibited HSP20-centered proteostasis; and adults predominantly expressed HSP40 together with multiple HSP70 members, accompanied by enrichment of stress response and metamorphosis-related functions. This study provides new insights into developmental transcriptional regulation, metabolic remodeling, and stage-specific specialization of molecular chaperone networks in H. armigera, establishing a foundation for future studies of stress adaptation, population genomic variation, and developmental mechanisms.

Cotton bollworm↗

PubMed2026

Hepatic metabolic adaptation to endurance exercise: temporal and sex differences by multiomics integration and validation.

BACKGROUND: Although endurance exercise benefits liver health, sex-specific adaptive trajectories remain unclear. This study mapped dynamic liver adaptation in males and females during prolonged training and identified underlying molecular programs. METHODS: Using publicly available time-resolved liver multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we established a computational pipeline for differential analysis of transcriptomic, proteomic, phosphoproteomic, and metabolomic data with FDR correction, followed by FGSEA pathway enrichment. Kinase activities were inferred through ortholog mapping and PhosphoSitePlus. Cross-omics co-expression networks were constructed using WGCNA and topological overlap to link omics features with physiological phenotypes. For experimental validation, liver tissues were collected from endurance-trained Sprague-Dawley rats, and key nodes were confirmed by Western blotting, qRT-PCR, and immunofluorescence/immunohistochemical staining. Public scRNA-seq data were further integrated to map multi-omics signals to single-cell resolution and assess functional changes in specific cell types. RESULTS: The hepatic response to exercise stress was stage-specific, shifting from early transcriptional activation to later proteomic and metabolic remodeling. Multi-omics integration revealed distinct sex-associated adaptive trajectories: males were more strongly associated with energy metabolism, redox-related programs, and amino acid/organic acid catabolism, whereas females showed prominent membrane lipid remodeling, proteostasis -related programs, and mitochondrial/ribosomal translational features. Single-cell analysis showed that tissue remodeling occurred without major lineage turnover, instead involving altered communication among pre-existing cell communities. Validation of PPP1R3G identified a protein-dominant exercise-responsive marker, supporting the contribution of post-transcriptional or protein-level regulation. CONCLUSIONS: Hepatic adaptation to endurance stress follows a cross-omics evolutionary pattern with sex-specific reprogramming of energy supply and homeostatic maintenance. This time-resolved framework clarifies how exercise improves liver function and supports sex-oriented metabolic interventions and therapeutic target discovery.

Animals↗

PubMed2024

Clocking out and letting go to unleash green biotech applications in a photosynthetic host.

Cyanobacteria are photosynthetic bacteria whose gene expression patterns are globally regulated by their circadian (daily) clocks. Due to their ability to use sunlight as their energy source, they are also attractive hosts for "green" production of pharmaceuticals, renewable fuels, and chemicals. However, despite the application of traditional genetic tools such as the identification of strong promoters to enhance the expression of heterologous genes, cyanobacteria have lagged behind other microorganisms such as Escherichia coli and yeast as economically efficient cell factories. The previous approaches have ignored large-scale constraints within cyanobacterial metabolic networks on transcription, predominantly the pervasive control of gene expression by the circadian (daily) clock. Here, we show that reprogramming gene expression by releasing circadian repressor elements in the transcriptional regulatory pathways coupled with inactivation of the central oscillating mechanism enables a dramatic enhancement of expression in cyanobacteria of heterologous genes encoding both catalytically active enzymes and polypeptides of biomedical significance.

Photosynthesis↗

PubMed2025

Cross-species phenotypic profiling uncovers functional determinants of bacterial cold shock adaptation.

Temperature shifts impose broad physiological stress, requiring precise and dynamic regulatory programs to restore cellular homeostasis. While the heat shock response is well characterized, the mechanisms underlying cold shock response (CSR) remain less understood. To identify genes critical for cold adaptation, we applied transposon sequencing (Tn-seq) to monitor mutant fitness across the full course of CSR and sustained low-temperature growth in two mesophilic bacteria, Escherichia coli and Bacillus subtilis. In B. subtilis, phenotypic profiling revealed a temporally structured program: membrane fluidity and cell wall remodeling were most critical in the early stage of CSR, whereas post-transcriptional regulation became essential during late-stage recovery to reprogram gene expression and restore growth. Cross-species comparison uncovered both conserved and species-specific mechanisms, with RNA metabolism and ribosome/translation regulators playing broad roles. Specifically, we identified a conserved synergy between two ribosomal RNA methyltransferases, RsmA and RsmH, in promoting cold adaptation. In B. subtilis, mutants lacking these enzymes exhibited significant delay in translation recovery following cold-induced global inhibition. Together, these findings provide a comparative, systems-level view of bacterial cold adaptation and establish a framework for exploring stress responses in pathogens and extremophiles.

Cell envelope↗

PubMed2026

Dysregulated adult hippocampal neurogenesis in major depressive disorder.

Major depressive disorder (MDD) is associated with reduced hippocampal volume, altered connectivity and negative memory bias, suggesting disrupted hippocampal plasticity. Dysregulated adult hippocampal neurogenesis is a potential contributor, but its relevance in humans and role in MDD remain unclear. Here we investigated the molecular basis of hippocampal dysfunction in nonmedicated individuals with MDD by integrating analyses of neurogenic trajectories, cell-type- and subfield-specific gene expression, chromatin accessibility and protein expression. We identify a neurogenic lineage in the adult human hippocampal subgranular zone and provide evidence for a stalled neurogenic process in MDD, associated with transcriptional regulation, stress-related reprogramming and interferon signaling across developmental stages. Excitatory and inhibitory neurons show dysregulation of transcription factor networks affecting cell states. Cellular stress, excitatory-inhibitory imbalance, impaired synaptic plasticity, reduced metabolic capacity and immune activation, underlie impaired neurogenesis and reduced hippocampus circuit plasticity. Findings indicate genetic and epigenetic regulation of gene expression in MDD, and overlapping pathogenetic mechanisms with autoimmune, neurodevelopmental and neurodegenerative diseases. This work provides a new understanding of the pathogenesis of hippocampus-dependent cognitive symptoms in MDD and suggests potential therapeutic targets.

Journal Article↗

PubMed2026

Transcriptomic insights into exogenous fatty acid-enhanced halotolerance in Zygosaccharomyces rouxii.

BACKGROUND: High salinity restricts microbial growth during brine-based food fermentation. Although exogenous unsaturated fatty acids improve the salt tolerance of Zygosaccharomyces rouxii, the associated transcriptional mechanisms remain unclear. This study investigated the transcriptomic response of Z. rouxii CGMCC 3791 to palmitoleic acid (C16:1) under high salt conditions. RESULTS: Cells were cultured in yeast extract peptone dextrose (YPD) containing 120 g L-1 NaCl, with or without 20 μg mL-1 C16:1. They were analyzed by RNA sequencing. Principal component analysis clearly separated the two treatments. Using q < 0.05 and |log2 fold change| > 1, 23 differentially expressed genes were identified - three upregulated and 20 downregulated. INO1, MLS1, POX1, MEP2, and SOD5 were among the major responsive genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that peroxisome-associated functions, lipid metabolism, oxidative stress responses, nitrogen utilization, and mitogen-activated protein kinase (MAPK) signaling were the principal C16:1-responsive processes. CONCLUSION: Exogenous C16:1 elicited a focused transcriptional adjustment rather than broad transcriptome-wide reprogramming in salt-stressed Z. rouxii. The results indicated that peroxisome-linked lipid processes and redox regulation were candidate mechanisms underlying fatty-acid-associated halotolerance and provided targets for improving the robustness of high-salt food fermentation. © 2026 Society of Chemical Industry.

Zygosaccharomyces rouxii↗

PubMed2026

CD36 Influences Leukemia Progression in MLL-AF9-Driven AML by Modulating the Leukemia Immune Microenvironment.

CD36, a fatty-acid translocase, is increasingly implicated in acute myeloid leukemia biology and treatment resistance, yet its contribution to leukemogenesis is still unclear. Using the MLL-AF9 model, we transduced hematopoietic stem/progenitor cells (HSPCs) from Cd36-knockout (KO) or wild-type (WT) mice and assessed leukemic potential with in vitro assays, transplants, and transcriptomic, metabolomic, and immune profiling. Both Cd36KO- and Cd36WT-HSPCs underwent efficient MA9-driven transformation, with comparable colony formation and Hox/Meis1 pathway activation, indicating Cd36 is dispensable for leukemic initiation. However, Cd36 deletion markedly attenuated disease progression, reducing leukemic burden and extending survival in irradiated mice (median 22 vs. 15 days, P = 0.001). Effects were strikingly amplified in immunocompetent, non-irradiated recipients (median 63 vs. 22 days, P = 0.002), revealing immune-dependent suppression. Immune profiling showed enhanced CD4⁺ and CD8⁺ T cell infiltration, reduced CD4⁺CD25⁺ regulatory-like cells, and lower Tim-3 expression in Cd36KO-MA9 spleens, consistent with a less exhausted, more effective anti-leukemic T cell response. Despite enhanced T cell infiltration, TCR repertoires remained conserved, indicating functional reprogramming rather than clonal selection. Consistent with a suppressive leukemia immune microenvironment, RNA-seq gene set enrichment analysis identified upregulation of inflammatory (TNFα/NF-κB) and hypoxic pathways in Cd36WT-MA9 cells. Untargeted metabolomics revealed metabolic shifts in Cd36KO cells, involving a reduction in three key metabolites, UDP-GlcNAc, UDP-Galactose/UDP-Glucose, and O-Phospho-L-Serine, that likely support an immune evasion mechanism. These findings demonstrate that while Cd36 is not essential for MLL-AF9-mediated transformation, its cell-intrinsic expression in leukemic cells suppresses anti-leukemic immunity and accelerates progression. This positions CD36 as a promising target to enhance immune surveillance and limit AML aggressiveness.

Acute Myeloid Leukemia (AML)↗

PubMed2026

A voyage of reprogrammable metabolic bioengineering reshapes plant defense: from editing tools to synthetic systems.

Metabolic bioengineering has emerged as a transformative approach for reshaping plant defense by targeting intrinsic biosynthetic pathways to enhance immunity in modern agriculture. Moving beyond proof-of-concept metabolomics to broad-spectrum programmable pathway engineering addresses gaps in plant rational design and optimizes resilience in response to diverse environmental cues. This review aims to comprehensively highlight the transition of innovative approaches to phenolics, alkaloids, flavonoids, terpenoids, and benzoxazinoids, inferring adaptive reprogramming that mediates the growth-defense balance and functions as molecular sentinels in plants. Furthermore, decoding the volatile metabolome reveals a dynamic signaling interface that influences defense responses and stress-induced plant-microbe interactions, with the shikimate, jasmonate, and salicylate pathways functioning as central hubs for microbial deterrence and priming immune memory. Recent developments in multi-scalar genome-editing strategies, including CRISPR-driven combinatorial edits, enzyme orthogonalization, fluxomics, and spatially resolved multi-omics, reconfigure central and specialized metabolic fluxes toward improved defense function and regulation. Additionally, emerging tools, such as WUSCHEL2 and BABY BOOM transcriptional modules, and artificial engineering strategies integrating deep learning model-driven predictions facilitate rapid development of synthetic genetic circuits and support a predictive engineering of plants. Moreover, Mass spectrometry imaging (MSI) in spatial metabolomics enables to obtain structures and locations of unidentified endogenous metabolites within cells and tissues. Overall, this review emphasizes a diverse array of primary and secondary metabolites, spanning molecular concepts to recent advances in plant immune mechanisms. It also illustrates new frontiers in programmable metabolic engineering that accelerate the understanding of plant-microbe-metabolite cross-talks, offering strategies to improve plant resistance and advance sustainable agricultural solutions.

metabolic bioengineering↗

PubMed1990

Evaluation of rate-responsive pacemakers by transesophageal Holter monitoring of spontaneous atrial rate.

One of the most important problems in rate responsive (RR) pacing is the clinical experimental evaluation of the reliability of various sensors. In particular, it is difficult to test their sensitivity and specificity during daily activity of the patients. Atrial rate, when present and normal, is the most physiological marker of metabolic requirements, but sometimes it is impossible to analyze the P wave in ventricular paced rhythm during routinely performed tests (e.g., ergometric test and 24-hour Holter monitoring). During various physical activities, we monitored atrial electrograms on an esophageal lead on the first channel of a standard Holter tape recorder; on the second channel a surface ECG lead was recorded. We selected 10 patients with high grade heart block and normal sinus node function paced in RR-VVI mode. RR pacing was obtained using various sensors (body activity, blood temperature, spike-T interval, minute ventilation). The good quality of recording allowed an easy evaluation of atrial and ventricular rates. In four cases an appropriate increase in heart rate was documented; sensitivity threshold and/or rate response slope were reprogrammed when indicated. The pacing rate of one patient did not parallel the atrial rate during walking only. In three cases, we observed a delay in the ventricular rate increase, with ventricular rate decreasing at peak exercise despite further atrial rate increase. In the last two patients, we observed inappropriate pacing response; pacing rate increased later and to a lower level than the atrial one. This new method is applied easily and appears reliable to evaluate the response of RR pacemakers to individual metabolic needs.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed2026

Targeting ncRNA control networks with engineered exosomes to overcome therapy resistance in thyroid cancer.

Papillary thyroid cancer (PTC) is the most prevalent endocrine malignancy, accounting for over 90% of thyroid cancers. While differentiated thyroid cancers (DTCs) typically have favorable outcomes, a significant subset progresses to radioactive iodine-refractory (RAIR) disease, characterized by impaired iodine uptake and a 10-year survival rate below 10%. Genetic alterations and dysregulated signaling pathways underlie this transition. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), play critical regulatory roles in tumor biology and may be transported via exosomes, facilitating intercellular communication and contributing to RAIR-PTC. This systematic review, conducted according to PRISMA 2020 guidelines, evaluated the role of exosomal ncRNAs in RAIR-PTC. A comprehensive search of PubMed, PubMed Central, and Google Scholar identified studies published within the past 15 years in English. Following stringent quality appraisal, studies with a non-bias score above 40% were included. Of 961 identified publications, 96 high-quality studies met inclusion criteria. Evidence indicates that therapy resistance in RAIR-PTC is driven by convergent ncRNA regulatory networks that suppress sodium-iodide symporter (NIS) expression and activate oncogenic pathways, most notably MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling. Multiple ncRNAs converge on key regulatory nodes, forming redundant circuits that sustain dedifferentiation, metabolic adaptation, and impaired iodide transport. Several consistently dysregulated ncRNAs directly or indirectly regulate NIS expression and trafficking, highlighting actionable targets. Exosomes emerge as biologically compatible, programmable delivery vehicles capable of transporting therapeutic ncRNA payloads independent of endogenous packaging mechanisms. These findings support a precision therapeutic paradigm in which engineered exosomes reprogram ncRNA networks to restore iodine-handling pathways and overcome therapy resistance in RAIR-PTC.

Humans↗

PubMed2026

Establishment of human induced pluripotent stem cell lines and isogenic gene-corrected controls from three patients with prolidase deficiency.

Prolidase deficiency is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the PEPD gene. To date, close to 200 patients have been reported worldwide with a poorly understood pathomechanism. The PEPD gene encodes an enzyme that is involved in the final steps of collagen degradation. Urine amino acid analysis or specific dipeptide analysis can establish the biochemical diagnosis. In this study, we reprogrammed peripheral blood mononuclear cells (PBMCs) from three prolidase deficient patients into induced pluripotent stem cell (iPSC) lines and additionally generated isogenic controls using CRISPR-Cas9 genome editing. The pathogenic PEPD variants identified in our patients were NP_000276.2:p.? (NIHTVBi032-A), NP_000276.2:p.(Ile415Asn)/NP_000276.2:p.(Trp326Ter) (NIHTVBi033-A), and NP_000276.2:p.(Arg265Ter) (NIHTVBi034-A). These iPSC lines are valuable models to help investigate the pathomechanism of prolidase deficiency.

Humans↗

PubMed1976

Epidermal cell development during the pupal-adult metamorphosis of Hyalophora cecropia.

To establish a base for studying the hormonal control of insect epidermal cell activity, the ultrastructure of abdominal epidermis was analyzed during the normal pupal-adult development of Hyalophora cecropia. Adjacent epidermal cells could be distinguished on the basis of organelle content and staining intensity, suggesting that this monolayer is not composed of a homogenous cell population. At the onset of adult development the form of the epidermal cell is transformed from that typical of a quiescent cell with free ribosomes and few mitochondria to one which is metabolically active and possesses numerous apical membrane microvilli, rough endoplasmic reticulum and numerous mitochondria. On about day 5 of pharate adult development the apical plasma membrane is no longer folded but becomes folded again several days later when cuticulin and endocuticle are deposited. On about day 7, giant autophagic vacuoles are discerned that may be important in cellular reprogramming. After adult ecdysis, the epidermal cells continue to deposit endocuticle.

Animals↗

PubMed2026

Proteomic and phosphoproteomic profiles of time-dependent dynamic changes in LPS-induced macrophage polarization.

The temporal proteomic and phosphoproteomic reprogramming during early M1 macrophage polarization (0-6 h) remains poorly understood. We performed time-resolved proteomic and phosphoproteomic analyses of LPS-stimulated RAW264.7 macrophages at seven time points within 6 h. Time-clustering of differentially expressed molecules revealed two patterns: initial change with partial recovery, and sustained dysregulation. Upregulated proteins and phosphorylation sites were enriched in the Rho GTPase signaling pathway, T-cell receptor signaling pathway, NF-κB cascade, osteoclast differentiation pathway, and antiviral immune pathway. Downregulated pathways were associated with cell cycle regulation, chromatin remodeling, RNA metabolism, and mRNA processing, indicating resource reallocation to prioritize acute inflammatory responses. Kinase-substrate network analysis confirmed the mitogen-activated protein kinase (MAPK), cyclin-dependent kinase (CDK), protein kinase B (AKT), and ribosomal S6 kinase (RSK) families as core upstream phosphorylation regulators. Integrated analysis revealed synergistic and antagonistic relationships between proteomic and phosphoproteomic changes. This study provides a temporal molecular atlas of M1 polarization, delineating inflammatory signaling dynamics and offering a basis for therapeutic target discovery in inflammatory diseases. SIGNIFICANCE: Macrophage M1 polarization is a central event in innate immune defense against pathogenic invasion, yet its dysregulation is a pivotal driver of the onset and progression of a broad spectrum of inflammation-associated disorders, spanning autoimmune diseases, infectious conditions and inflammatory bone diseases, making the dissection of its molecular regulatory mechanisms an urgent research priority in immunology and translational medicine. Dynamic molecular events within 0-6 h after LPS stimulation are critical for initiating and shaping M1 inflammatory activation, yet systematic time-resolved proteomic and phosphoproteomic profiling remains insufficient.In this study, we comprehensively characterized temporal proteome and phosphoproteome changes at seven consecutive time points during macrophage polarization, clarified two distinct dynamic molecular patterns, identified core signaling pathways and key kinase regulators involved in inflammatory reprogramming, and uncovered the leading role of post-translational phosphorylation modifications in initiating polarization. This work delineates the time-series molecular atlas of early macrophage activation, provides novel insights into the temporal regulatory mechanism of inflammatory signaling networks, and lays a solid experimental foundation for exploring new intervention targets and regulatory nodes in clinical translational research.

Lipopolysaccharides↗

PubMed2025

Reprogramming neuroblastoma by diet-enhanced polyamine depletion.

Neuroblastoma is a highly lethal childhood tumour derived from differentiation-arrested neural crest cells1,2. Like all cancers, its growth is fuelled by metabolites obtained from either circulation or local biosynthesis3,4. Neuroblastomas depend on local polyamine biosynthesis, and the inhibitor difluoromethylornithine has shown clinical activity5. Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumour differentiation and profound survival gains in the Th-MYCN mouse model. Specifically, an arginine- and proline-free diet decreases the amount of the polyamine precursor ornithine and enhances tumour polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at codons with adenosine in the third position. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by combined dietary and pharmacological intervention, favours a pro-differentiation proteome. These results suggest that the genes of specific cellular programmes have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of paediatric cancers.

Animals↗

PubMed2025

Plasma Proteomic Profiling Reveals ITGA2B as A Key Regulator of Heart Health in High-altitude Settlers.

Myocardial injury is a common disease in the plateau, especially in the lowlanders who have migrated to the plateau, in which the pathogenesis is not well understood. Here, we established a cohort of lowlanders comprising individuals from both low-altitude and high-altitude areas and conducted plasma proteomic profiling. Proteomic data showed that there was a significant shift in energy metabolism and inflammatory response in individuals with myocardial abnormalities at high altitude. Notably, integrin alpha-Ⅱb (ITGA2B) emerged as a potential key player in this context. Functional studies demonstrated that ITGA2B upregulated the transcription and secretion of interleukin-6 (IL-6) through the integrin-linked kinase (ILK)/nuclear factor-κB (NF-κB) signaling axis under hypoxic conditions. Moreover, ITGA2B disrupted mitochondrial structure and function, increased glycolytic capacity, and aggravated energy reprogramming from oxidative phosphorylation to glycolysis. Leveraging the therapeutic potential of traditional Chinese medicine in cardiac diseases, we discovered that tanshinone ⅡA (TanⅡA) effectively alleviated the myocardial injury caused by the abnormally elevated expression of ITGA2B and hypobaric hypoxia exposure in mice, thus providing a novel candidate therapeutic strategy for the prevention and treatment of high-altitude myocardial injury.

Animals↗