PubMed

Front Mol Biosci. 2025 Mar 13;12:1553162. doi: 10.3389/fmolb.2025.1553162. eCollection 2025.ABSTRACTBACKGROUND: Chenpi (the dried mature peel of Citrus reticulata Blanco) and Rougui (the dried bark of Cinnamomum cassia Presl) are both edible and medicinal plants, which have therapeutic effects on nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms necessitate further exploration. This study evaluated the prevention effect of Chenpi-Rougui herb pair (CRP) on NAFLD using an integrated strategy that combined network pharmacology with metabolomics.METHODS: Initially, the components in CRP decoction were characterized by UPLC-QTOF-MS/MS. Subsequently, a high-fat diet induced NAFLD mouse model was used to assess the efficacy of CRP and its individual constituent, Chenpi and Rougui. Additionally, synergetic pathways and crucial targets for CRP therapy in NAFLD were identified using network pharmacology and serum metabolomics. Finally, real-time polymerase chain reaction (RT-PCR) was utilized to validate relevant genes.RESULTS: CRP exerted a more extensive prevention effect on NAFLD mice compared to the individual herb of Chenpi and Rougui. A total of 105 compounds were characterized from CRP, which were linked to 70 potential therapeutic targets for NAFLD. Thirty-two differential metabolites were identified by metabolomics, which were co-regulated by Chenpi, Rougui and CRP. Pathways associated with the intervention of herb pair in NAFLD included energy metabolism, fatty acid metabolism, glycerophospholipid metabolism, sphingolipids metabolism, arachidonic acid metabolism, sterol and bile acid metabolism. Finally, eight targets were screened through conjoint analysis and experimental verification showed that six of them including FASN, AKT1, CASP3, F2, PTGS2 and PRKCA, could be modulated by CRP in NAFLD mice. Besides, Chenpi primarily regulated FASN, AKT1, CASP3 and PRKCA, which were associated with reducing apoptosis in hepatocytes, while Rougui exceled in regulating F2 and PTGS2, closely linked to its anti-inflammatory properties. The combination of Chenpi and Rougui resulted in a broader influence on metabolites, pathways, and primary targets compared to their individual application.CONCLUSION: These results provided valuable insights into the compatibility mechanism of CRP for treating NAFLD, and could also improve the value of its forthcoming application and development as a natural liver protective agent.PMID:40182620 | PMC:PMC11966411 | DOI:10.3389/fmolb.2025.1553162

Front Mol Biosci. 2025 Mar 20;12:1515276. doi: 10.3389/fmolb.2025.1515276. eCollection 2025.ABSTRACTINTRODUCTION: Exploiting microbial natural products is a key pursuit of the bioactive compound discovery field. Recent advances in modern analytical techniques have increased the volume of microbial genomes and their encoded biosynthetic products measured by mass spectrometry-based metabolomics. However, connecting multi-omics data to uncover metabolic processes of interest is still challenging. This results in a large portion of genes and metabolites remaining unannotated. Further exacerbating the annotation challenge, databases and tools for annotation and omics integration are scattered, requiring complex computations to annotate and integrate omics datasets.METHODS: Here we performed a two-way integrative analysis combining genomics and metabolomics data to describe a new approach to characterize the marine bacterial isolate BRA006 and to explore its biosynthetic gene cluster (BGC) content as well as the bioactive compounds detected by metabolomics.RESULTS AND DISCUSSION: We described BRA006 genomic content and structure by comparing Illumina and Oxford Nanopore MinION sequencing approaches. Digital DNA:DNA hybridization (dDDH) taxonomically assigned BRA006 as a potential new species of the Micromonospora genus. Starting from LC-ESI(+)-HRMS/MS data, and mapping the annotated enzymes and metabolites belonging to the same pathways, our integrative analysis allowed us to correlate the compound Brevianamide F to a new BGC, previously assigned to other function.PMID:40182618 | PMC:PMC11965639 | DOI:10.3389/fmolb.2025.1515276

Front Plant Sci. 2025 Mar 20;16:1547157. doi: 10.3389/fpls.2025.1547157. eCollection 2025.ABSTRACT'Egusi' melon (Colocynthis citrullus L.) plays a critical role in food security and potential biofuel production in West Africa. Its seeds are valued for both their nutritional and potential industrial applications, especially in biodiesel production. However, the crop faces significant challenges, including the impacts of climate change, water scarcity, declining arable land, and increased pressure from pests and diseases. These challenges threaten the stability of 'Egusi' production and may hinder its ability to meet future demand. To address these issues, there is a growing need to complement conventional breeding methods with biotechnological approaches. Molecular approaches; including genomics, transcriptomics, proteomics, and metabolomics; have been utilized for the improvement of several cucurbit species. However, information on molecular breeding of 'Egusi' is very limited. The current review focuses on 'Egusi' melon, its biology, uses, and factors affecting its improvement, and highlights critical knowledge gaps in the molecular breeding of 'Egusi'. The review also examines the potential of omics technologies and outlines the importance of genetic transformation and genome editing methods such as CRISPR that could drive the development of more resilient and high-yielding 'Egusi'varieties that will contribute to sustainability and profitability of 'Egusi' farming.PMID:40182542 | PMC:PMC11965695 | DOI:10.3389/fpls.2025.1547157

RSC Adv. 2025 Apr 3;15(13):10419-10425. doi: 10.1039/d5ra01441g. eCollection 2025 Mar 28.ABSTRACTDespite ongoing efforts to employ structure-based methods to discover targeted protein degraders (TPD), the prevailing strategy continues to be the synthesis of a focused set of heterobifunctional compounds and screening them for target protein degradation. Here we used a fluorescence based live cell imaging screen to identify degraders that target exon 14 skipped hepatocyte growth factor receptor (MET). MET is a known oncogenic driver. MET exon 14 skipping mutations (METex14Δ) are found in lung cancers and result in the loss of a degron that is required for E3-ligase recognition and subsequent ubiquitination, prolonging the half-life and oncogenicity of MET. Since proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that promote target degradation by the proteosome, we sought to restore degradation of MET lost with METex14Δ using a MET-targeting PROTAC. We generated a library of sixty PROTACs of which 37 used the MET inhibitor capmatinib as the protein of interest targeting ligand. We screened this PROTAC library for targeted degradation of METex14Δ-GFP using live cell imaging. We benchmarked the MET-targeting PROTACs to that of a previously reported MET-targeting PROTAC, SJF8240. Curve fitting live cell imaging data affords determination of time required to degrade 50% of the target protein (DT50), which was used in determining structure activity relationships. A promising candidate, 48-284, identified from the screen, exhibited classic PROTAC characteristics, was >15-fold more potent than SJF8240, had fewer off targets compared to SJF8240, and degraded MET in multiple cell lines.PMID:40182503 | PMC:PMC11967169 | DOI:10.1039/d5ra01441g

Front Immunol. 2025 Mar 20;16:1567833. doi: 10.3389/fimmu.2025.1567833. eCollection 2025.ABSTRACTIdiopathic inflammatory myopathies (IIMs) are heterogeneous autoimmune disorders characterized by muscle inflammation, weakness, and extramuscular manifestations such as interstitial lung disease, skin rash, arthritis, dysphagia, myocarditis and other systemic organ involvement. Although T and B cells have historically been central to the understanding of IIM immunopathology, monocytes and their differentiated progenitor cells, macrophages, are increasingly being recognized as critical mediators of both tissue damage and repair. In subtypes such as dermatomyositis, immune-mediated necrotizing myopathy and antisynthetase syndrome, macrophages infiltrate skeletal muscle and other affected tissues, contributing to inflammation via production of pro-inflammatory cytokines, chemokines, and reactive oxygen species. Dysregulated interferon signaling, mitochondrial stress, and aberrant metabolic states in these cells further perpetuate tissue injury in IIMs. Conversely, certain macrophage subsets can support muscle fiber regeneration and dampen inflammation, underscoring the dual roles these cells can play. Future research into the heterogeneity of monocytes and macrophages, including single-cell transcriptomic and metabolomic approaches, will help clarify disease mechanisms, identify biomarkers of disease activity and prognosis, and guide novel therapeutic strategies targeting these innate immune cells in IIM.PMID:40181992 | PMC:PMC11965591 | DOI:10.3389/fimmu.2025.1567833

Front Immunol. 2025 Mar 20;16:1548735. doi: 10.3389/fimmu.2025.1548735. eCollection 2025.ABSTRACTGiven the inevitable hypoxia and reperfusion injury that occur in organs donated after circulatory death (DCD), the quality and function of these organs are significantly compromised, greatly limiting their application in clinical organ transplantation. Recently, the advancement of functional omics technologies has enabled us to deeply analyze the mechanisms underlying DCD donor organ damage from multiple perspectives. This review systematically integrates the studies from transcriptomics, proteomics, and metabolomics to reveal the key biological mechanisms associated with the declines in DCD donor organ quality, including oxidative stress, inflammatory responses, cell death pathways, and metabolic disturbances. Additionally, we summarized emerging therapeutic strategies based on findings from omics perspectives, offering new possibilities to improve the quality of DCD organ for better transplant prognosis. Finally, we discussed the challenges in current research and future directions to provide scientific evidence for clinical practice and promote the application of DCD donors in organ transplantation.PMID:40181961 | PMC:PMC11965662 | DOI:10.3389/fimmu.2025.1548735

J Anim Sci Biotechnol. 2025 Apr 4;16(1):50. doi: 10.1186/s40104-025-01182-0.ABSTRACTBACKGROUND: Rumen microorganisms are key regulators of ruminant growth and production performance. Identifying probiotic candidates through microbial culturomics presents a promising strategy for improving ruminant production performance. Our previous study identified significant differences in rumen microbial communities of Holstein calves with varying average daily gain (ADG). This study aims to identify a target strain based on the findings from multi-omics analysis and literature review, isolating and evaluating the target microbial strains from both the rumen and hindgut contents for their probiotic potential.RESULTS: Parabacteroides distasonis, a strain closely associated with ADG, was successfully isolated from calf rumen content cultured with Fastidious Anaerobe Agar (FAA) medium and named Parabacteroides distasonis F4. Whole-genome sequencing and pan-genome analysis showed that P. distasonis F4 possesses a core functional potential for carbohydrate and amino acid metabolism, with the ability to produce propionate, acetate, and lactate. The results of targeted and untargeted metabolomics further validated the organic acid production and metabolic pathways of P. distasonis F4. An in vitro simulated rumen fermentation test showed that supplementation with P. distasonis F4 significantly altered rumen microbial community structure and increased the molar proportions of propionate and butyrate in the rumen. Furthermore, an in vivo study demonstrated that dietary supplementation with P. distasonis F4 significantly increased the ADG of pre-weaning calves.CONCLUSIONS: This study represents the first isolation of P. distasonis F4 from rumen, highlighting its potential as a probiotic strain for improving rumen development and growth performance in ruminants.PMID:40181465 | DOI:10.1186/s40104-025-01182-0

BMC Oral Health. 2025 Apr 3;25(1):476. doi: 10.1186/s12903-025-05847-0.ABSTRACTBACKGROUND: Spleen-stomach damp-heat syndrome is one of the most common syndrome types in periodontitis from traditional Chinese medicine theory. However, its pathological mechanism is still uncertain. Tissue metabolism is driven by microbes in the host and its microenvironment. Hostmicrobe-metabolism is an interacting and closely related complex. Lipid metabolomics can find lipid metabolites in disease or healthy state, which is beneficial to explore the metabolic process and change mechanism of lipids that may be involved in organisms in healthy or disease state from the perspective of systems biology.METHODS: In this study, 10 patients in the periodontitis group (CP), 10 patients in the periodontitis with spleen-stomach dampness-heat syndrome group (SP) and 10 patients in the healthy group (H) were recruited for participation, whose unstimulated saliva was collected. The differential metabolites between the groups were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and screened out based on the variable importance in projection (VIP) combined with the P-value and fold change (FC) value of univariate analysis. Finally, KEEG pathway enrichment analysis was performed on these differential metabolites.RESULTS: A total of 1131 metabolites were detected in saliva in this study. 497 metabolites were significantly up-regulated in periodontitis, mainly plasma-membrane-associated lipids, unsaturated fatty acids and oxidized lipids. Compared with the healthy group, the lipid metabolism pathways of periodontitis with or without spleen-stomach dampness-heat syndrome group were mainly characterized by significant enrichment of glycerophospholipid metabolism and unsaturated fatty acid metabolism such as arachidonic acid metabolism.CONCLUSION: Compared with periodontally healthy patients, periodontitis with or without spleen-stomach dampness-heat syndrome can cause changes in lipid metabolism in saliva samples of patients. These metabolites are mainly plasma membrane lipids, unsaturated fatty acids and oxidized lipids quality. These lipids may be potential biomarkers of periodontitis. The downstream metabolites of unsaturated fatty acids in the saliva samples of patients with periodontitis and spleen-stomach dampness-heat syndrome were abnormal, and the oxidized lipid (±)5-HETE was significantly abnormal. We speculate that this may be related to the increased state of oxidative stress in saliva samples in disease states.PMID:40181453 | DOI:10.1186/s12903-025-05847-0

BMC Oral Health. 2025 Apr 3;25(1):480. doi: 10.1186/s12903-025-05792-y.ABSTRACTOBJECTIVE: Saliva, which is a critical component of the oral ecosystem, undergoes dynamic changes, particularly during the onset and progression of periodontitis.SUBJECTS AND METHODS: This study used Gas Chromatography-Mass Spectrometry (GC-MS), a reliable and high-throughput tool for metabolomic analysis, to detect salivary metabolic shifts across various stages of periodontitis (T1-T4). We compared differential changes in metabolites between the HC and T1 groups, the T1 and T2 groups, the T2 and T3 groups, and the T3 and T4 groups.RESULTS: By analysing saliva samples from 116 individuals-10 healthy controls (HC) and 106 patients with periodontitis across stages T1 (22 individuals) to T4 (28 individuals), we identified differential metabolites including Glucose, 3-Aminobutanoic Acid, N-(1-Cyclopropylethyl) Aniline, and Methylmalonic Acid. Compared to HC, the metabolites in patients with periodontitis exhibited progressive concentration changes correlating with the severity of the disease. Furthermore, KEGG pathway analysis was used to elucidate the metabolic pathways involved in the development of periodontitis.CONCLUSIONS: Our findings demonstrate the potential of salivary metabolites as biomarkers for monitoring periodontitis progression and offer valuable insights into its pathogenesis and potential therapeutic targets.PMID:40181365 | DOI:10.1186/s12903-025-05792-y

Autophagy. 2025 Apr 3. doi: 10.1080/15548627.2025.2488563. Online ahead of print.ABSTRACTEndurance exercise triggers adaptive responses especially in slow-twitch myofibers of skeletal muscles, leading to the remodeling of myofiber structure and the mitochondrial network. However, molecular mechanisms underlying these adaptive responses, with a focus on the fiber type-specific perspective, remains largely unknown. In this study we analyzed the alterations of transcriptomics and metabolomics in distinct skeletal myofibers in response to endurance exercise. We determined that genes associated with sphingolipid metabolism, namely those encoding SPHK1, S1PR1, and S1PR2, are enriched in slow-twitch but not fast-twitch myofibers from both mouse and human skeletal muscles, and found that the SPHK1-S1PR pathway is essential for adaptive responses of slow-twitch to endurance exercise. Importantly, we demonstrate that endurance exercise causes the accumulation of ceramides on stressed mitochondria, and the mitophagic degradation of ceramides results in an increase of the sphingosine-1-phosphate (S1P) level. The elevated S1P thereby facilitates mitochondrial adaptation and enhances endurance capacity via the SPHK1-S1PR1/S1PR2 axis in slow-twitch muscles. Moreover, administration of S1P improves endurance performance in muscle atrophy mice by emulating these adaptive responses. Our findings reveal that the SPHK1-S1P-S1PR1/S1PR2 axis through mitophagic degradation of ceramides in slow-twitch myofibers is the central mediator to endurance exercise and highlight a potential therapeutic target for ameliorating muscle atrophy diseases.PMID:40181214 | DOI:10.1080/15548627.2025.2488563

Nat Chem. 2025 Apr 3. doi: 10.1038/s41557-025-01789-w. Online ahead of print.ABSTRACTMicrobiota-mediated drug metabolism can affect pharmacological efficacy. Here we conducted a systematic comparative metabolomics investigation of drug metabolism modes by evaluating the impacts of human gut commensal bacteria on 127 G-protein-coupled receptor (GPCR)-targeted drugs. For the most extensively metabolized drugs in our screen, we elucidated both conventional and unconventional drug transformations and the corresponding activities of generated metabolites. Comparisons of drug metabolism by a gut microbial community versus individual species revealed both taxon intrinsic and collaborative processes that influenced the activity of the metabolized drugs against target GPCRs. We also observed iloperidone inactivation by generating unconventional metabolites. The human gut commensal bacteria mixture incorporated sulfur in the form of a thiophene motif, whereas Morganella morganii used a cascade reaction to incorporate amino-acid-derived tricyclic systems into the drug metabolites. Our results reveal a broad impact of human gut commensal bacteria on GPCR-targeted drug structures and activities through diverse microbiota-mediated biotransformations.PMID:40181149 | DOI:10.1038/s41557-025-01789-w

Sci Rep. 2025 Apr 3;15(1):11502. doi: 10.1038/s41598-025-96038-y.ABSTRACTThis study investigates the role of Cathepsin D (CTSD) in diabetic vascular complications, particularly its impact on the phenotypic transformation of vascular smooth muscle cells (VSMCs) induced by advanced glycation end-products (AGEs), and explores its potential molecular mechanisms. CTSD was overexpressed in VSMCs using lentiviral vectors. Various methods, including CCK-8, immunofluorescence, SA-β-Gal staining, EdU assay, scratch assay, cell cycle analysis, and Western blotting, were employed to assess VSMC viability, proliferation, migration, senescence, and apoptosis. Additionally, transcriptomic and metabolomic analyses were conducted to investigate the molecular mechanisms underlying CTSD overexpression in VSMCs. AGEs treatment significantly inhibited CTSD expression in VSMCs, leading to reduced cell viability, enhanced proliferation and migration, increased senescence, and apoptosis. In contrast, overexpression of CTSD effectively inhibited AGEs-induced VSMCs proliferation, migration, senescence, and apoptosis. Combined transcriptomic and metabolomic analyses suggested that CTSD may affect VSMCs phenotypic transformation by inhibiting the glycolysis pathway. This study highlights the critical role of CTSD in the phenotypic transformation of VSMCs induced by AGEs and provides a new perspective for cardiovascular and cerebrovascular disease treatment. CTSD may emerge as a novel therapeutic target, though its specific molecular mechanisms and clinical application prospects in VSMCs phenotypic transformation require further investigation.PMID:40181129 | DOI:10.1038/s41598-025-96038-y

Nat Commun. 2025 Apr 3;16(1):3174. doi: 10.1038/s41467-025-58525-8.ABSTRACTAnchorage-independent survival of ovarian tumor cells in ascites is the initial and critical step for peritoneal metastasis. How ovarian tumor cells achieve anchorage independence remains unclear. Here we show that a noncanonical role of spermidine/spermine N1-acetyltransferase 1 (SAT1) dictates anchorage-independent cell survival and potentiates metastatic dissemination in ovarian cancer. SAT1-high cancer cells are prevalent in ascitic tumors, and high SAT1 expression in primary tumors is linked to increased peritoneal metastasis rates in ovarian cancer patients. Mechanistically, SAT1 noncanonically acetylates H3K27 domains in multiple mitosis-regulating genes, increasing their transcriptional levels and protecting disseminating cells from aberrant mitosis and mitotic cell death. Notably, the acetylation of H3K27 by SAT1 depends on the reductive carboxylation of glutamine to supply acetyl-CoA in the nucleus. SAT1 inhibition with the small-molecule inhibitor ginkgolide B attenuates the metastatic tumor burden in mouse models. We conclude that SAT1 inhibition is a promising therapeutic strategy for metastatic ovarian cancer.PMID:40180916 | DOI:10.1038/s41467-025-58525-8

Semin Nephrol. 2025 Apr 2:151577. doi: 10.1016/j.semnephrol.2025.151577. Online ahead of print.ABSTRACTThe coupling between energy metabolism and transport processes is a key feature that defines the functional capability of proximal tubule cells. Recent studies using metabolomics and transcriptomics provide insights into the relationships between changes in single-cell transcriptomic profiles and energy metabolism during kidney development and in disease states. In this review, we describe insights from these studies and how mapping of metabolites to functional pathways within cells enables these insights. We also describe our analyses of fatty acid metabolism pathways from single-cell transcriptomic data obtained by the Kidney Precision Medicine Project, which indicate that proximal tubule cell subtypes can be divided into two major groups with high and low levels of mRNAs for fatty acid (beta) oxidation enzymes. On average, patients with CKD have higher levels of cells with low fatty acid oxidation capability. These cells also have lower levels of sodium transporters. Within each group of proximal tubule cell subtypes there is considerable variability between individual patients. Integrating these data with metabolomics analyses can provide insights into how the differential metabolic capabilities of proximal tubule cells are related to disease features in individual patients. Identifying such relationships can lead to development of precision medicine approaches in nephrology.PMID:40180882 | DOI:10.1016/j.semnephrol.2025.151577

J Steroid Biochem Mol Biol. 2025 Apr 2:106741. doi: 10.1016/j.jsbmb.2025.106741. Online ahead of print.NO ABSTRACTPMID:40180878 | DOI:10.1016/j.jsbmb.2025.106741

Methods Cell Biol. 2025;195:143-172. doi: 10.1016/bs.mcb.2023.03.007. Epub 2023 Jul 14.ABSTRACTFlow cytometry has great potential for screening in translational research areas due to its deep quantification of cellular features, ability to collect millions of cells in minutes, and consistently expanding suite of validated antibodies that detect cell identity and functions. However, cytometry remains under-utilized in discovery chemical biology due to the differences in expertise between chemistry groups developing chemical libraries and cell biologists developing single cell assays. This chapter is designed to bridge this gap by providing a detailed protocol aimed at both chemistry and biology audiences with the goal of helping train novice researchers. Assay users select from three elements: a small molecule input, a target cell type, and a module of cytometry readouts. For each, we explore basic and advanced examples of inputs, including screening fractionated microbial extracts and pure compounds, and target cells, including primary human blood cells, mouse cells, and cancer cell lines. One such module of cytometry readouts focuses on cell function and measures DNA damage response (γH2AX), growth (phosphorylated S6), DNA content, apoptosis (cleaved Caspase3), cell cycle M phase (phosphorylated Histone H3), and viability (membrane permeabilization). The protocol can also be adapted to measure different functional readouts, such as cell identity or differentiation and contrasting cell injury mechanisms. The protocol is designed to be used in 96-well plate format with fluorescent cell barcoding and the debarcodeR algorithm. Ultimately, the goal is to encourage the next generation of chemical biologists to use functional cell-based cytometry assays in discovery and translational research.PMID:40180452 | DOI:10.1016/bs.mcb.2023.03.007

Environ Res. 2025 Apr 1:121517. doi: 10.1016/j.envres.2025.121517. Online ahead of print.ABSTRACTAs an emerging pollutant, the synthetic cannabinoid N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (ADB-FUBINACA) is widely abused and frequently detected in metropolitan wastewater. However, its effect on aquatic organisms remains unexplored. In this study, embryonic and larval zebrafish were exposed to sublethal concentrations of ADB-FUBINACA to assess its toxic effects via behavioral, biochemical, and metabolomic analyses. The observed morphological defects included reduced heartbeat, shorter body length, spinal deformation, and pericardial edema. Transgenic zebrafish exhibited cardiac developmental defects and apoptosis, indicating that cardiotoxicity is associated with dysregulated gene expression. Impaired motor activity and disrupted neuronal development suggested neurotoxicity. Elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels indicate oxidative stress, whereas transcriptional changes in immune-related genes reflect a dysregulated inflammatory response. Metabolomic analyses revealed disruptions in pathways related to alanine, purine, and pyrimidine metabolism, and arginine biosynthesis, which correlated with oxidative damage, cardiotoxicity, and neurodevelopmental effects. In conclusion, ADB-FUBINACA induces developmental toxicity in zebrafish embryos via oxidative stress and metabolic disruption, highlighting the potential environmental risks posed by this emerging pollutant.PMID:40180266 | DOI:10.1016/j.envres.2025.121517

Mol Metab. 2025 Apr 1:102132. doi: 10.1016/j.molmet.2025.102132. Online ahead of print.ABSTRACTOBJECTIVE: Liver fibrosis is a crucial condition for evaluating the prognosis of chronic liver disease. Lectin-1ike oxidized low density lipoprotein receptor-1 (LOX-1) has been shown potential research value and therapeutic targeting possibilities in different fibrotic diseases. However, the role of LOX-1 and the underlying mechanisms in liver fibrosis progression remain unclear.METHODS: LOX-1 expression was detected in liver tissues from patients and rodents with liver fibrosis. LOX-1 knockout rats were subjected to CCl4 or methionine and choline-deficient diet (MCD) to induce liver fibrosis. Transcriptomic and metabolomics analysis were used to investigate the involvement and mechanism of LOX-1 on liver fibrosis.RESULTS: We found that LOX-1 exacerbated liver fibrosis by promoting hepatic stellate cells (HSCs) activation. LOX-1 deletion reversed the development of liver fibrosis. We further verified that LOX-1 drove liver fibrosis by reprogramming glutamine metabolism through mediating isoform switching of glutaminase (GLS). Mechanistically, we revealed the crucial role of the LOX-1/OCT1/GLS1 axis in the pathogenesis of liver fibrosis. Moreover, LOX-1 rewired ammonia metabolism by regulating glutamine metabolism-urea cycle to drive the progression of liver fibrosis.CONCLUSIONS: Our findings uncover the pivotal role of LOX-1 in the progression of liver fibrosis, enrich the pathological significance of LOX-1 regulation of hepatic ammonia metabolism, and provide an insight into promising targets for the therapeutic strategy of liver fibrosis, demonstrating the potential clinical value of targeting LOX-1 in antifibrotic therapy.PMID:40180177 | DOI:10.1016/j.molmet.2025.102132

Toxicology. 2025 Apr 1:154131. doi: 10.1016/j.tox.2025.154131. Online ahead of print.ABSTRACTCopper oxide nanoparticles (CuO NPs) are increasingly used in various industrial fields, and the toxicity of CuO NPs raises concerns. However, the CuO NPs-induced pulmonary inflammation and the underlying mechanism have not been fully illustrated. Cellular cuproptosis provides a new perspective to elucidate the toxicity of CuO NPs. Here, we exposed C57BL/6 mice and murine alveolar macrophage cells (MH-S) to CuO NPs, respectively. A suspension of 2mg/mL CuO NPs was directly once administered by intratracheal instillation, and mice were sacrificed on day 7. The histopathology results showed that CuO NPs induced pulmonary inflammation in C57BL/6 mice. CuO NPs increased Cu2+ levels by 203.0% in mouse lung tissues. Also, CuO NPs increased the cuproptosis-related indicators of ferredoxin (FDX1), dihydrolipoamide succinyltransferase (DLST), dihydrolipoamide acetyltransferase (DLAT) and Cu transporter 1 (CTR1) in both mouse lung tissues and MH-S cells. Transcript sequencing and non-targeted metabolomics indicated that CuO NPs induced cellular cuproptosis and inflammatory responses both in vivo and in vitro. Interleukin-17a (IL-17A) was remarkably increased in the process of CuO NPs-induced cellular cuproptosis. Additionally, interference of FDX1 reduced cellular cuproptosis and decreased the release of IL-17A. In summary, CuO NPs increased the accumulation of intracellular Cu2+ and the expressions of cuproptosis-related proteins, induced FDX1-mediated cuproptosis, and led to pulmonary inflammation in mice. This study highlights the respiratory toxicity of CuO NPs and reveals a unique cuproptosis-driven mechanism underlying the CuO NPs-induced pulmonary inflammation.PMID:40180017 | DOI:10.1016/j.tox.2025.154131

Neuroimmunomodulation. 2025 Apr 3:1-15. doi: 10.1159/000545484. Online ahead of print.ABSTRACTThe gut microbiota is increasingly recognized as a critical regulator of brain function, influencing neurodevelopment, adult brain physiology, and disease vulnerability in part through its interactions with microglia, the resident immune cells of the central nervous system. Emerging evidence demonstrates that microbial metabolites, beginning prenatally and persisting throughout the lifespan, regulate fundamental aspects of microglial biology including maturation, metabolic function, and activation. Microglia from germ-free mice exhibit persistent immaturity, altered energy metabolism, and blunted inflammatory responses, which are partially reversible by restoring microbial communities or supplementing key microbial metabolites. Short-chain fatty acids, tryptophan-derived indoles, and other bacterial metabolites derived from the gut microbiota shape microglial function to modulate neurons and synaptic architecture, and influence neuroinflammatory processes. These findings reveal distinct metabolite-driven pathways linking microbial composition to microglial phenotypes, positioning the microbiome as a potential key influencer of neurodevelopmental trajectories and the pathophysiology of psychiatric and neurological disorders. Despite recent advances, major knowledge gaps persist in understanding the precise molecular intermediaries and mechanisms through which metabolite signaling to microglia shape neural function to influence susceptibility or resilience to brain-based disorders. Understanding both the bacterial metabolomic landscape and its collective impact on microglial programming holds substantial therapeutic promise, offering avenues to target microbial metabolite production or administer them directly to modulate brain health.PMID:40179831 | DOI:10.1159/000545484