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PubMed2026

Targeting Microbial Bile Salt Hydrolase Reprograms Bile Acid Metabolism and Ameliorates Metabolic Dysfunction-Associated Steatohepatitis in Mice.

Microbial bile salt hydrolase (BSH) plays a central role in shaping bile acid composition and gut-liver metabolic signaling, yet its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) remains incompletely defined. Here, we evaluated the efficacy of the non-absorbable BSH inhibitor GR-7 in a diet induced mouse model of steatohepatitis using early and late intervention strategies with different dosing regimens. GR-7 reduced food intake and exerted stage- and dose-dependent therapeutic effects, with early intervention robustly suppressing hepatic fibrosis even at low dose, whereas late-stage administration of high-dose GR-7 markedly reduced hepatic steatosis and inflammation, as evidenced by decreased liver weight, hepatic triglyceride and cholesterol levels, and plasma ALT. Although late intervention did not result in statistically significant histological reversal of fibrosis, a trend toward improvement was observed, together with suppression of fibrogenic gene expression, suggesting that prolonged treatment may further enhance antifibrotic efficacy. Mechanistically, GR-7 effectively inhibited microbial BSH activity in vivo, leading to reduced cecal unconjugated primary and secondary bile acids-including deoxycholic acid and lithocholic acid, which was associated with improved gut barrier integrity and reduced hepatic inflammation. In parallel, BSH inhibition reprogrammed hepatic bile acid metabolism toward activation of the alternative CYP27A1-mediated synthesis pathway, accompanied by reduced food intake, thereby contributing to improved hepatic lipid accumulation. Furthermore, late-stage high-dose treatment selectively remodeled the hepatic immune landscape rather than fully restoring homeostasis, highlighting immune recalibration as a key component of therapeutic response. Together, these findings identify microbial BSH inhibition as a promising microbiome-targeted therapeutic strategy for MASH.

Gut microbiome↗
PubMed2026

Targeting microbial bile salt hydrolase reprograms bile acid metabolism and ameliorates metabolic dysfunction-associated steatohepatitis in mice.

Microbial bile salt hydrolase (BSH) plays a central role in shaping bile acid composition and gut-liver metabolic signaling, yet its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) remains incompletely defined. Here, we evaluated the efficacy of the non-absorbable BSH inhibitor GR-7 in a diet-induced mouse model of steatohepatitis using early and late intervention strategies with different dosing regimens. GR-7 reduced food intake and exerted stage- and dose-dependent therapeutic effects, with early intervention robustly suppressing hepatic fibrosis even at a low dose, whereas late-stage administration of high-dose GR-7 markedly reduced hepatic steatosis and inflammation, as evidenced by decreased liver weight, hepatic triglyceride and cholesterol levels, and plasma ALT. Although late intervention did not result in statistically significant histological reversal of fibrosis, a trend toward improvement was observed, together with suppression of fibrogenic gene expression, suggesting that prolonged treatment may further enhance antifibrotic efficacy. Mechanistically, GR-7 effectively inhibited microbial BSH activity in vivo, leading to reduced cecal unconjugated primary and secondary bile acids-including deoxycholic acid and lithocholic acid, which was associated with improved gut barrier integrity and reduced hepatic inflammation. In parallel, BSH inhibition reprogrammed hepatic bile acid metabolism toward activation of the alternative CYP27A1-mediated synthesis pathway, accompanied by reduced food intake, thereby contributing to reduced hepatic lipid accumulation. Furthermore, late-stage high-dose treatment selectively remodeled the hepatic immune landscape rather than fully restoring homeostasis, highlighting immune recalibration as a key component of therapeutic response. Together, these findings identify microbial BSH inhibition as a promising microbiome-targeted therapeutic strategy for MASH.

Animals↗
PubMed2001

The transcriptional activator Cat8p provides a major contribution to the reprogramming of carbon metabolism during the diauxic shift in Saccharomyces cerevisiae.

In yeast, the transition between the fermentative and the oxidative metabolism, called the diauxic shift, is associated with major changes in gene expression and protein synthesis. The zinc cluster protein Cat8p is required for the derepression of nine genes under nonfermentative growth conditions (ACS1, FBP1, ICL1, IDP2, JEN1, MLS1, PCK1, SFC1, and SIP4). To investigate whether the transcriptional control mediated by Cat8p can be extended to other genes and whether this control is the main control for the changes in the synthesis of the respective proteins during the adaptation to growth on ethanol, we analyzed the transcriptome and the proteome of a cat8 Delta strain during the diauxic shift. In this report, we demonstrate that, in addition to the nine genes known as Cat8p-dependent, there are 25 other genes or open reading frames whose expression at the diauxic shift is altered in the absence of Cat8p. For all of the genes characterized here, the Cat8p-dependent control results in a parallel alteration in mRNA and protein synthesis. It appears that the biochemical functions of the proteins encoded by Cat8p-dependent genes are essentially related to the first steps of ethanol utilization, the glyoxylate cycle, and gluconeogenesis. Interestingly, no function involved in the tricarboxylic cycle and the oxidative phosphorylation seems to be controlled by Cat8p.

Carbon↗
PubMed2026

Patient-specific modeling identifies metabolic interventions for reversing glucose use reprogramming in alcohol-associated hepatitis.

Alcoholic hepatitis (AH) is an acute form of alcohol-associated liver disease with very few treatment options. Recent studies highlighted liver metabolic reprogramming in AH as an indicator of severity. We aim at identifying new intervention points to reverse liver metabolic dysregulation across varying degrees of AH. We develop 89 personalized genome-scale metabolic models by integrating a generic human cellular metabolic model with liver transcriptomics data from AH patients with varying disease severity and healthy controls. We grade the AH patients based on the model-predicted level of glycolysis reprogramming and validate the results using published metabolomics data. We test in silico gene knockdown interventions to reverse the aberrant metabolic reprogramming in AH. Knockdown of two glycolytic genes, Hkdc1 and Pkm, significantly rebalance the metabolic fluxes toward a healthy liver metabolic phenotype. We use machine learning on the glycolysis fluxes to develop a quantitative glucose use reprogramming score, which correlates with AH severity and patient-specific responses to in silico gene knockdown interventions. The score was independently validated using a published AH liver transcriptomics dataset. We propose a cellular metabolism-based therapy targeting Hkdc1 and Pkm in the glycolysis pathway as a potential treatment for reversing the aberrant glucose metabolism in AH.

Humans↗
PubMed2026

Macrophage plasticity and metabolic control in muscle repair and disease.

Inflammation is a tightly regulated process essential for skeletal muscle repair, and its dysregulation contributes to chronic disease and impaired regeneration. Following injury, muscle repair involves a coordinated immune response initiated by neutrophil infiltration, followed by macrophage recruitment and diversification. Rather than existing as discrete subsets, macrophages span a continuum of functional states that evolve over time in response to local environmental cues, enabling transitions from clearing debris and pro-inflammatory signaling to supporting resolution of inflammation, and remodeling and regeneration of the tissue. This functional plasticity is closely linked to intracellular metabolic programs. In this review, we examine how metabolic pathways, particularly the balance between glycolysis and oxidative phosphorylation, govern macrophage behavior through epigenetic mechanisms, thereby coupling cellular metabolism to inflammatory and regenerative gene expression. We further explore how these interconnected pathways are disrupted in chronic inflammatory muscle diseases, including muscular dystrophies. Recent transcriptomic studies highlight pathogenic macrophage populations with altered metabolic and epigenetic profiles that contribute to fibrosis and impaired regeneration. By integrating findings from both acute injury and chronic disease contexts, we provide a framework to explore macrophage function through a metabolic and epigenetic lens and discuss emerging strategies aimed at restoring macrophage plasticity and promoting the resolution of inflammation in muscle disease.

Humans↗
PubMed2026

Oxidative stress and cancer: current insights and therapeutic implications.

OXIDATIVE STRESS: good or evil? Oxidative stress occurs when the balance between reactive oxygen species (ROS) and antioxidant defenses shifts toward an excess of ROS; while essential in physiological processes, it plays a context-dependent role in cancer, contributing to both the promotion and inhibition of tumorigenesis. Small to moderate amounts of ROS activate pathways supporting tumor progression and proliferation, while large amounts lead to genomic instability and cell death. ROS are generated endogenously and exogenously. In cancer, ROS activate pathways that prompt tumor development (KRAS, MYC, PI3K-Akt-mTOR) and block tumor suppressors (p53, BRCA1), allowing tumorigenesis and drug resistance. They also modulate the tumor microenvironment (TME) by altering tumor, stromal and immune cell interactions, which initiate angiogenesis, epithelial-mesenchymal transition (EMT), inflammation and metastasis. Myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) contribute to ROS-driven immunosuppression. Cancer cells mainly rely on glycolysis and oxidative phosphorylation (OXPHOS) to sustain their energetic and metabolic requirements. Generated ROS act as metabolic byproducts and signaling molecules supporting proliferation and tumorigenesis. Cancer stem cells (CSCs) produce low ROS levels by activating antioxidant pathways and mitochondria remodeling, ensuring recurrence and persistence. There is a redox duality that presents challenges and opportunities for therapies. Pro-oxidant approaches attempt to overwhelm the tumor's defenses, while antioxidants preserve healthy tissues. Advances in targeted redox modulation with immunotherapies improve therapy effectiveness. We propose a new "Adaptive Directed Redox Therapy" (ADRT), which involves a dynamic, feedback-controlled methodology that alternates pro- and antioxidant phases to selectively collapse tumor redox balance while preserving normal tissues.

Humans↗
PubMed2002

Dynamic flux balance analysis of diauxic growth in Escherichia coli.

Flux Balance Analysis (FBA) has been used in the past to analyze microbial metabolic networks. Typically, FBA is used to study the metabolic flux at a particular steady state of the system. However, there are many situations where the reprogramming of the metabolic network is important. Therefore, the dynamics of these metabolic networks have to be studied. In this paper, we have extended FBA to account for dynamics and present two different formulations for dynamic FBA. These two approaches were used in the analysis of diauxic growth in Escherichia coli. Dynamic FBA was used to simulate the batch growth of E. coli on glucose, and the predictions were found to qualitatively match experimental data. The dynamic FBA formalism was also used to study the sensitivity to the objective function. It was found that an instantaneous objective function resulted in better predictions than a terminal-type objective function. The constraints that govern the growth at different phases in the batch culture were also identified. Therefore, dynamic FBA provides a framework for analyzing the transience of metabolism due to metabolic reprogramming and for obtaining insights for the design of metabolic networks.

Cell Division↗
PubMed2026

Epithelial-Mesenchymal Transition Shapes the Lipotoxic Response of Colon Cancer Cells to Palmitic Acid.

Saturated fatty acids such as palmitic acid (PA) can induce lipotoxic stress, whereas monounsaturated fatty acids like oleic acid (OA) often promote adaptive responses through lipid droplets (LDs) formation. Here, we reveal that epithelial-mesenchymal transition (EMT) profoundly influences the lipotoxic response of colorectal cancer cells. Using the epithelial-like HCT15 and mesenchymal-like HCT116 cell lines, we combined proteomic, metabolic, and imaging analyses to elucidate how EMT status determines lipid storage capacity and resistance to PA-induced toxicity. A basal proteomic profiling highlighted a striking divergence in metabolic changes: HCT15 cells displayed enhanced glycolysis and reduced expression of LDs biogenesis proteins, while HCT116 cells exhibited oxidative metabolism and a "lipid-rich" proteomic signature enriched in PLIN2, GPAT3, and DGAT1. Functionally, PA triggered massive cytotoxicity and failed to induce LDs in HCT15 cells, correlating with DGAT1/2 downregulation and suppressed triacylglycerol synthesis. In contrast, HCT116 cells showed modest LDs accumulation, preserved mitochondrial function, and strong resistance to lipotoxic stress. OA treatment restored LDs formation and cell viability in both models, underscoring the protective role of unsaturated fatty acids. Notably, forced EMT induction in HCT15 cells by PMA markedly enhanced LDs accumulation and reduced PA-induced death, confirming that EMT confers metabolic plasticity and lipid-buffering capacity. These findings demonstrate that EMT status modulates differential lipid handling and stress adaptation in colon cancer cells, linking mesenchymal transition to enhanced LDs biogenesis and survival under lipotoxic conditions. Data are available via ProteomeXchange with identifier PXD071641.

Humans↗
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↗
PubMed1997

Regulation of metabolism and growth during immune challenge: an overview of cytokine function.

Commercially reared food animals encounter serial pathogenic and nonpathogenic immune challenges throughout production. Because of the diversion of nutrients away from growth in support of immune-related processes, immune challenge is considered a major obstacle to animals' achieving their genetic potential for growth or efficiency of gain. Scientists now recognize that many metabolic processes respond directly or indirectly to proinflammatory cytokines. This cytokine-mediated "reprogramming" of metabolism is a homeorhetic mechanism that ensures an adequate supply of nutrients for proliferation of lymphocyte and macrophage populations, antibody production, and hepatic synthesis of acute phase proteins. Proinflammatory cytokines have been linked to altered nutrient uptake and utilization. Anabolic processes are interrupted, and companion catabolic activities are amplified. Furthermore, cytokines may influence prenatal growth and development, and to the extent that postnatal proliferation and differentiation of myogenic and adipogenic cells contribute to postnatal growth, cytokine regulation of these events may ultimately influence growth. The following discussion is an overview of the impact of immune challenge and proinflammatory cytokines on metabolism and growth.

Acute-Phase Proteins↗
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↗
PubMed1996

Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack.

We develop a unifying theory of hypoxia tolerance based on information from two cell level models (brain cortical cells and isolated hepatocytes) from the highly anoxia tolerant aquatic turtle and from other more hypoxia sensitive systems. We propose that the response of hypoxia tolerant systems to oxygen lack occurs in two phases (defense and rescue). The first lines of defense against hypoxia include a balanced suppression of ATP-demand and ATP-supply pathways; this regulation stabilizes (adenylates) at new steady-state levels even while ATP turnover rates greatly decline. The ATP demands of ion pumping are down-regulated by generalized "channel" arrest in hepatocytes and by "spike" arrest in neurons. Hypoxic ATP demands of protein synthesis are down-regulated probably by translational arrest. In hypoxia sensitive cells this translational arrest seems irreversible, but hypoxia-tolerant systems activate "rescue" mechanisms if the period of oxygen lack is extended by preferentially regulating the expression of several proteins. In these cells, a cascade of processes underpinning hypoxia rescue and defense begins with an oxygen sensor (a heme protein) and a signal-transduction pathway, which leads to significant gene-based metabolic reprogramming-the rescue process-with maintained down-regulation of energy-demand and energy-supply pathways in metabolism throughout the hypoxic period. This recent work begins to clarify how normoxic maintenance ATP turnover rates can be drastically (10-fold) down-regulated to a new hypometabolic steady state, which is prerequisite for surviving prolonged hypoxia or anoxia. The implications of these developments are extensive in biology and medicine.

Adenosine Monophosphate↗
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↗
PubMed2003

A functional genomics approach toward the understanding of secondary metabolism in plant cells.

Despite the tremendous importance of secondary metabolites for humans as for the plant itself, plant secondary metabolism remains poorly characterized. Here, we present an experimental approach, based on functional genomics, to facilitate gene discovery in plant secondary metabolism. Targeted metabolite analysis was combined with cDNA-amplified fragment length polymorphism-based transcript profiling of jasmonate-elicited tobacco Bright yellow 2 cells. Transcriptome analysis suggested an extensive jasmonate-mediated genetic reprogramming of metabolism, which correlated well with the observed shifts in the biosynthesis of the metabolites investigated. This method, which in addition to transcriptome data also generates gene tags, in the future might lead to the creation of novel tools for metabolic engineering of medicinal plant systems in general.

Acetates↗