Biology subjects

Wang, K.

Publications and source records attributed to Wang, K..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Time-dependent bistability leads to critical slowing down during floral transition in Arabidopsis

Developmental transitions occur in the life cycles of all multicellular organisms. Despite their fundamental relevance, the underlying dynamics remain poorly understood. In plants, floral transition is a key developmental process whereby the shoot apical meristem changes from producing leaves to forming flowers. Using quantitative imaging, developmental genetics and dynamical systems theory, we show that a time-dependent bistable switch between expression of APETALA2, a key floral inhibitor, and the floral activators SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 and FRUITFULL, can explain the dynamics of floral transition in Arabidopsis. Notably, we detect a slowing down of the inhibitor dynamics, consistent with the system crossing a critical point of a bistable switch and transiently experiencing a ghost attractor. We demonstrate that this time-dependent bistability is essential to generate the range of dynamical behaviours measured across genotypes, including oscillations in the inhibitor, and that it also confers robustness in the transition. Collectively, our work provides quantitative evidence of time-dependent bistability underlying floral transition, which introduces a new timescale to this developmental process.

systems biology↗

bioRxiv2025

Unified Probabilistic Analysis of CyTOF: A Deep Generative Approach using CytoOne

Extracting meaningful biological signals from Cytometry by time-of-flight (CyTOF) data remains challenging due to heterogeneity, data characteristics, and the presence of various technical artifacts. Current analysis workflows typically rely on task-specific tools assembled into pipelines, which often make inconsistent distributional assumptions and fail to fully leverage the structure of the data. We present CytoOne, a unified probabilistic framework tailored for CyTOF data that integrates batch correction, differential analysis, and visualization within a single model. CytoOne is built upon a Bayesian hierarchical architecture inspired by Nouveau Variational Autoencoders (NVAE) and employs a novel quasi zero-inflated softplus-normal (QZIPN) likelihood to flexibly model the sparse and noisy nature of CyTOF measurements. We demonstrate via qualitative and quantitative evaluations that CytoOne effectively approximates both marginal and joint distributions of CyTOF data, removes batch-specific artifacts, enables fine-grained differential expression analysis, and facilitates interpretable embeddings for exploratory analysis.

bioinformatics↗

bioRxiv2025

Regulation of Renal Transporters by Pro-inflammatory Cytokines in Human Proximal Tubular Epithelial Cells: Identification of the Perpetrator and Mechanisms

IntroductionInfection and inflammation elevate circulating pro-inflammatory cytokines that can affect renal drug clearance. Accordingly, we sought to (i) quantify the extent of modulation of renal drug-metabolizing enzymes and transporters (DMETs) by cytokines and (ii) identify the mechanism(s) underlying these effects. MethodsFresh primary human proximal tubular epithelial cells (PTECs) were cultured on extracellular matrix-coated Transwells. PTECs were exposed every 24 h, for 48 h, to IL-6, IL-1{beta}, TNF-, IFN-{gamma}, IL-4, or IL-10 (0.1 or 1 ng/mL), individually or as a cocktail. mRNA expression of 25 renal DMETs was quantified by RT-qPCR. Individual activity of OAT1-4, OCT2, and OCTN1 was measured. To determine mechanisms of these effects, selective MAPK/NF-{kappa}B inhibitors (ERK [PD98059], p38MAPK [SB203580], JNK [SP600125], and NF-{kappa}B [PDTC]), individually or as a cocktail, were used. IL-6, soluble IL-6 receptor (sIL-6R), and IL-6 + sIL-6R were used to probe endogenous/exogenous IL-6 classic versus trans-signaling. ResultsIL-1{beta} was the predominant modulator, downregulating mRNA expression of OAT1-3, OCT2, OAT4, MATE2-K, MRP2, and OATP4C1, and upregulating mRNA expression of OCTN1 and MRP3. TNF- downregulated OAT1-3 mRNA expression to an extent similar to IL-1{beta}, but did not affect other transporters. Activity changes for the major uptake transporters mirrored mRNA directionality. MAPK/NF-{kappa}B blockade by the inhibitor cocktail reduced IL-6 secretion while completely reversing the IL-1{beta}-driven downregulation of OAT1-3 mRNA. JNK inhibition alone restored OAT1/3 mRNA. Inhibition of p38MAPK blunted OAT2 mRNA downregulation. OCTN1 mRNA induction required NF-{kappa}B. Downregulation of OAT4/OCT2 mRNA was largely MAPK/NF-{kappa}B-independent. IL-6 alone, sIL-6R alone, or IL-6 + sIL-6R did not reproduce IL-1{beta}-driven changes in transporter mRNA. ConclusionsIL-1{beta} is the principal driver of cytokine-mediated regulation of human renal transporters in PTECs via JNK/p38MAPK/NF-{kappa}B nodes. These mechanistic, exposure-verified data provide inputs for physiologically based pharmacokinetic predictions of renal secretory clearance and pathway-mediated drug interactions during inflammation. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/690608v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@177e372org.highwire.dtl.DTLVardef@1f56bc4org.highwire.dtl.DTLVardef@17612e3org.highwire.dtl.DTLVardef@d2291f_HPS_FORMAT_FIGEXP M_FIG C_FIG Translational StatementSystemic inflammation increases cytokine concentrations and alters drug pharmacokinetics. Yet, cytokine regulation of renal drug transporters remains poorly defined, even though the kidney clears many anti-infective drugs via active secretion. Using an optimized primary human proximal tubular epithelial cell model that preserves expression and function of major renal transporters, we found that IL-1{beta} is the predominant cytokine that downregulates the mRNA and activity of OAT1-3, OCT2, and OAT4, while upregulating the mRNA and activity of OCTN1. We further showed that IL-1{beta}-driven downregulation of OAT1/3 occurs through JNK signaling, OAT2 through p38MAPK, and OCTN1 through NF-{kappa}B. These data provide quantitative inputs for physiologically based pharmacokinetic models to predict how inflammation alters renal transporter-mediated drug clearance, informing dose adjustment and risk assessment for disease-drug and drug-drug interactions in patients with inflammatory kidney disease or systemic infections. They also highlight signaling nodes where anti-inflammatory therapies might inadvertently modify renal drug transport.

pharmacology and toxicology↗

bioRxiv2025

De Novo Hepatic Pyrimidine Synthesis Regulates Systemic Energy Homeostasis

Fasting blood uridine is increased in obesity and type 2 diabetes (T2D), but the significance of hepatic uridine biosynthesis to the etiology of both remains elusive. We found that de novo pyrimidine synthesis in the liver is reduced by fasting and diet-induced obesity, while suppression of hepatic pyrimidine synthesis promotes obesity and insulin resistance. The metabolic sequalae of hepatic pyrimidine synthesis suppression, however, is not associated with altered plasma uridine concentration. Instead, it is associated with an increased hepatic glucose production and a decreased hepatic insulin clearance, two key functions of hepatocytes in regulating systemic energy homeostasis. We found that enhanced gluconeogenesis is the primary reason for increased hepatic glucose production. Moreover, uridine, which was maintained stable in the circulation by adipose tissue and the liver, preferentially shut down pyrimidine synthesis in hepatocytes but not adipocytes at blood concentrations that occur with fasting. Remarkably, uridine, at fasting levels, increases gluconeogenesis further in hepatocytes when de novo pyrimidine synthesis is suppressed, indicating a synergistical action of uridine and its biosynthesis pathway in promoting hepatic glucose production, a mechanism highly relevant to the pathophysiology of insulin resistance in obesity. Theologically, maintenance of blood uridine within the narrow range protects mammals from high-rate spontaneous tumorigenesis. Since obesity promotes an increase in blood uridine from adipocytes, suppressing uridine synthesis in hepatocytes becomes a critical response to lower spontaneous tumorigenesis. Pyrimidine synthesis suppression in hepatocytes, however, promotes gluconeogenesis and ultimately triggers obesity and T2D. These findings suggest a new paradigm for the etiology of metabolic deterioration in diet-induced obesity, in which perturbations in uridine promotes obesity and T2D.

pathology↗

bioRxiv2025

Gut Microbiota-derived Adenosine Determines the Efficacy of Electroconvulsive Therapy for Depression

Electroconvulsive therapy (ECT) is a final procedure for major depressive disorders (MDD). However, the effectiveness of ECT in treating MDD patients varies. Here we identified gut microbiota as a potential restraining factor of ECT efficacy. By using a 5-day electroconvulsive shock (ECS) in depression mouse model of chronic restraint stress (CRS), it was observed that the antidepressant effect of ECS was suppressed after antibiotics (ABX)-induced microbiota dysbiosis, which also resulted in elevated c-Fos expression of CRH neurons in paraventricular nucleus of hypothalamus (PVN) and increased serum corticosterone levels after ECS. Metabolomic analysis revealed the critical involvement of microbiota associated purine metabolism, and the supplement of gut microbiota-derived adenosine was able to recover the antidepressant effect of ECS in ABX-treated CRS mouse model. Based on the neural tracing from colon to brain and the immunofluorescence staining, it was surmised a gut-brain axis originated from Adora1-expressing cells in colon mediate this biological process. Furthermore, adenosine supplement alleviated the further deterioration of post-ECS memory loss and impairment of synaptic plasticity induced by ABX-treatment as well. Our findings suggest a potential role of microbial adenosine metabolism in ECT efficacy determination and side effect protection, highlights potential application of adenosine supplement in antidepressant therapies of those depression patients with microbiota dysbiosis.

systems biology↗

bioRxiv2025

Proteolytic activation of diverse antiviral defense modules in prokaryotes

Linked protease-effector modules are widespread in prokaryotic antiviral defense, yet the mechanisms of most remain poorly understood. Here we show that four of the most prevalent modules--metallo-{beta}-lactamase (MBL)-fold hydrolase, /{beta}-hydrolase, Pepco, and EACC1--form latent death effectors that are unleashed by site-specific proteolysis. Genetic, biochemical, and structural analyses reveal novel modes of effector licensing. MBL and /{beta}-hydrolase are zymogens activated by cleavage at two distinct sites, and upon proteolysis, MBL becomes a Zn2+-dependent double-stranded DNA nuclease. In contrast, Pepco and EACC1 act as pore-forming toxins via distinct mechanisms: Pepco constitutively oligomerizes into a denaturation-resistant beta barrel that is activated by cleavage after a specific isoleucine in its C-terminal tail, whereas EACC1 monomers assemble into large membrane pores following removal of an autoinhibitory domain. All four modules are fused to diverse sensors to detect a wide range of phage signals, and EACC1-DnaK chaperone fusions suggest a convergence between defense and general stress responses. These findings establish proteolysisgated activation as a dominant, modular logic for anti-phage defense and reveal parallels with eukaryotic innate immunity.

molecular biology↗

bioRxiv2025

Chicken IRF10 suppresses the cGAS-STING-IFN antiviral signaling pathway by targeting IRF7

The chicken (ch) innate immune cGAS-STING-IFN signaling pathway plays a crucial role in host antiviral defense, wherein chIRF7 serves as the key downstream transcription factor of chSTING responsible for initiating type I IFN transcription. While chicken IRF family encompasses 8 members, the potential involvement of other IRF members in chicken cGAS-STING-IFN signaling transduction and/or regulation remains poorly characterized. In this study, we identified chIRF10 as a potent suppressor of chicken cGAS-STING-IFN signaling against several viruses, by screening of chIRF family members. Mechanistically, the inhibitory activity of chIRF10 depended on its IRF associated domain (IAD) but not its DNA binding domain (DBD). Further, chIRF10 suppressed both cGAS-STING mediated IFN signaling and TBK1/IKK{varepsilon}/IRF7 activated IFN signaling. Importantly, chIRF10 could interact with chIRF7, and inhibit its dimerization and activation. In summary, our findings unveiled a novel function of chIRF10 as well as a novel regulatory mechanism governing chicken cGAS-STING-IFN antiviral signaling, thereby providing a scientific foundation for developing strategies against chicken viral diseases.

immunology↗

bioRxiv2025

Symmetric brain-liver circuits mediate lateralized regulation of hepatic glucose output

Neural lateralization is well recognized in the control of contralateral somatic movement, yet its relevance to visceral organ regulation remains poorly understood. This study aimed to determine whether the central nervous system exerts lateralized control over hepatic glucose metabolism and to localize the site of peripheral sympathetic crossover to the liver. Pseudorabies virus (PRV) tracing revealed bilateral projections from the lateral paragigantocellular nucleus (LPGi) with preferential innervation of the contralateral hepatic lobes. Unilateral LPGi activation elevated systemic glucose by enhancing glycogenolysis and gluconeogenesis specifically in contralateral lobes, whereas bilateral activation produced additive effects. Following unilateral hepatic denervation, contralateral LPGi activation induced metabolic compensation in the remaining innervated lobes, characterized by increased norepinephrine release, glucose production, and glycogen depletion. Whole-mount tissue clearing and dual viral tracing localized the sympathetic crossover to the porta hepatis. Developmental analysis showed that lobar-specific innervation along the vasculature emerges by postnatal week 2. These findings demonstrate that the brainstem can exert lobe-specific, lateralized control of hepatic glucose metabolism via bilaterally projecting brain - liver sympathetic pathways. This contralateral regulation arises from a peripheral decussation at the porta hepatis, and the compensatory activation observed after denervation reveals an intrinsic neuroadaptive mechanism that helps safeguard systemic glucose homeostasis. HighlightsO_LIBrain-liver sympathetic projections exhibit predominant contralateral innervation C_LIO_LIUnilateral LPGi activation drives glucose production in contralateral hepatic lobes C_LIO_LIUnilateral denervation augments contralateral LPGi-mediated metabolic compensation C_LIO_LISympathetic crossover to the liver localizes at the porta hepatis C_LI

neuroscience↗

bioRxiv2025

TMEM100 attenuates NF-κB activation via disrupting the PRDX1-GNAI2 complex to alleviate acute lung injury

Acute lung injury (ALI) is a severe and diffuse inflammatory disorder of interstitial lung. Emerging evidence suggests that TMEM100 is closely associated with lung development and function. However, its role in ALI remains unclear. In this study, we observed a significant downregulation of TMEM100 expression in both mouse lung tissues with ALI and lipopolysaccharide (LPS)-induced pulmonary vascular endothelial cells (PVECs). Overexpression of TMEM100 markedly attenuates LPS-induced lung injury and inflammation, while also restoring the imbalance between proliferation and apoptosis in PVECs. Mechanistically, TMEM100 interacts with both PRDX1 and GNAI2, disrupting the PRDX1-GNAI2 complex and thereby inhibiting LPS-induced NF-{kappa}B activation, which contributes to its anti-inflammatory effects. These findings highlight the protective role of TMEM100 in endotoxin-induced ALI and provide a theoretical basis for understanding its biological functions and potential applications in ALI gene therapy.

immunology↗

bioRxiv2025

Multiple Allosteric Sites Allow for Synergistic Enhancement of GPCR Signaling

Allosteric modulation of G protein-coupled receptors (GPCRs) is an emerging therapeutic paradigm that has proven effective, yet the cooperative action of multiple modulators remains unexplored. Here, we reveal how positive allosteric modulators (PAMs) synergistically enable extraordinary signal amplification through the D1 dopamine receptor (D1R). We developed UNC9815 and UNC10062 as enhanced D1R PAMs from the parent compound MLS6585, and then employed cryo-electron microscopy to reveal concurrent occupancy of three distinct allosteric sites by PAMs of different scaffolds, including LY3154207, BMS-A1, and our UNC compounds. Remarkably, we discovered two adjacent allosteric pockets at the transmembrane helix (TM) 1-7 interface: BMS-A1 occupies an intracellular site promoting activation through TM7 conformational shifts, while the UNC compounds complementarily stabilize the extracellular side of the interface. When combined with LY3154207, this cooperative architecture enhances dopamine potency by more than 1,000-fold. These findings elucidate the first structural blueprint for multi-site GPCR cooperativity, unlocking transformative therapeutic strategies inaccessible to orthosteric and single- site allosteric drugs.

molecular biology↗

bioRxiv2025

Coordination of local and global responses in individual mouse thalamic local interneurons

Inhibitory interneurons, featuring presynaptic release sites and spiking activity in dendrites, present a puzzle in their signal organization and coordination. We investigated this in local interneurons (LINs) of the primary visual thalamus using two-photon calcium imaging in awake mice with both local and full-screen visual stimuli. Dendrites in single LINs showed consistent global responses to full-screen stimuli but varied responses to local stimuli. Dendrites from the same LIN exhibited different receptive fields that followed retinotopic progression. The similarity between dendritic and somatic responses decreased with increasing distance. Weak local stimuli could excite dendrites locally, while salient local stimuli triggered global responses. Salient global stimuli further enhanced motion selectivity, preference consistency, and peak responses. Thus, LINs leverage both local and global dendritic activation to perform spatially-organized, feature-selective, and size-dependent motion processing, providing new insights into the complexity and precision of sensory processing in the early visual system. HighlightsO_LILocal interneurons (LINs) exhibit diverse yet sharp tuning to moving stimuli. C_LIO_LIdisplay an orderly shift of receptive field centers along their dendrites. C_LIO_LIThe propagation of calcium signals under local stimuli depends on stimulus strength. C_LIO_LIFull-screen stimuli enhance motion selectivity and peak responses. C_LI

neuroscience↗

bioRxiv2025

Fixing Hybrid Rice: >99% Efficient Apomixis with Near-Normal Seed Set

Apomixis, a form of clonal seed reproduction, offers a transformative approach to agriculture by enabling the stable fixation of hybrid vigor and elite heterozygosity across generations. However, the practical implementation of synthetic apomixis has been hindered by highly variable clonal efficiency or significant yield penalties. In this study, through integrated transcriptomic analyses, we identified a sperm-specific transcription factor in rice that likely functions as a key initiator of embryogenesis. Ectopic expression of this factor in egg cells effectively induces parthenogenesis and produces haploid progeny. When combined with clonal gametogenesis, this system achieved nearly complete synthetic apomixis, with clonal seed production rates exceeding 99% across all derived hybrid rice lines. Moreover, we generated apomictic hybrid lines that not only consistently produced over 99% clonal seeds but also exhibited seed yields comparable to conventional F1 hybrids. These findings establish a scalable and agriculturally viable platform for synthetic apomixis, achieving stable fixation of heterosis through clonal seeds and paving the way for the commercial deployment of self-perpetuating hybrid crops.

plant biology↗

bioRxiv2025

PubMind: Literature-Based Genetic Variant Extraction and Functional Annotation Using Large Language Models

The rapid growth of biomedical literature has produced extensive functional knowledge on genetic variants, much of which remains buried in unstructured texts. Current databases such as ClinVar and the Human Gene Mutation Database (HGMD) attempt to catalog this knowledge but have significant limitations: ClinVar depends on voluntary submissions and covers only a fraction of published literature, while the academic version of HGMD is updated infrequently and provides limited functional annotation. To address these gaps, we developed PubMind, an AI-driven multi-layer framework that uses large language models (LLMs) to extract variant- function-disease associations and supporting evidence from text. PubMind integrates a fine-tuned BERT model for input triage with instruction-tuned GPT models for inferring disease associations and functional annotations. The system captures diverse variant types--including SNVs, CNVs, SVs, and gene fusions--and normalizes records to genome and transcriptome coordinates. Benchmarking demonstrates >90% accuracy in variant recognition and 99% precision in disease extraction. Application of PubMind on >41 million PubMed abstracts and >5 million open-access full-text articles produced PubMind-DB, a database containing [~]1.3 million unique variants with rich contextual annotations, accessible via a web interface and API. Only [~]10% of PubMinds variants overlapped with ClinVar entries, yet >80% showed concordant pathogenicity labels, including full agreement with ClinVars expert-reviewed variants. Case studies demonstrate PubMind-DBs ability to uncover supporting evidence for variant pathogenicity that might otherwise be missed by manual searches. Together, these findings establish PubMind as a scalable LLM-based framework that transforms unstructured biomedical text into structured genomic knowledge, advancing variant interpretation for precision medicine.

bioinformatics↗

bioRxiv2025

A Structure-Guided Kinase-Transcription Factor Interactome Atlas Reveals Docking Landscapes of the Kinome

AbstractProtein kinases orchestrate cellular processes through phosphorylation, yet the structural basis for their specific binding partner interactions remains largely unmapped. Here, we present a structure-guided atlas of the human and Drosophila kinome, built by applying a new interface-aware scoring framework (iLIS) to AlphaFold-Multimer predictions. The resulting atlas recapitulates hallmark sequence preferences, confirms previously reported and functionally related protein-protein interactions, and uncovers unrecognized docking interactions. Notably, our analysis predicts a potentially widespread docking motif on homeodomain transcription factors that mediates interactions with basophilic kinases. Furthermore, we map putative allosteric interaction hotspots across the kinome and provide proof-of-concept evidence that targeting these surfaces can inhibit kinase activity. Finally, we demonstrate the physiological utility of the atlas by identifying a novel regulatory mechanism between Sgg/GSK3 and Hnf4 that controls lipid metabolism in vivo. This resource provides a blueprint for dissecting signaling networks and for the rational design of docking-site-specific kinase modulators.

bioinformatics↗

bioRxiv2025

BrAVe: a unified framework for 3D interactive and integrative analysis of cross-modal multi-scale brain atlas data in diverse species

Understanding the brain requires integrating molecular, structural, and functional information across multiple scales. Despite the rapid expansion of multimodal, multiscale brain atlases in various species, integrative analysis remains challenging. Here, we present iBrAVE, an open-source platform for 3D interactive, integrative analysis of brain atlas datasets across modalities and scales within a common reference space. iBrAVE unifies heterogeneous datasets into five core representations, enabling source-independent analyses from insects to primates. At the single-modality level, it features spatially resolved quantification, as exemplified by single-neuron morphology analyses spanning geometry, topology, projection, clustering, and putative wiring. Across modalities, it links gene expression and neuronal activity with morphologically defined neurons and putative circuits via establishing spatial correspondence. Across scales, it enables bidirectional inference of neuronal identity and synaptic connectivity between light- and electron-microscopy reconstructions via neuronal morphology matching. Thus, iBrAVE provides a unified framework for integrative brain atlas analyses, facilitating data-driven discovery in neuroscience.

neuroscience↗

bioRxiv2025

E- and N-cadherin drive hepatic polarity and lumen elongation via opposing effects on RhoA activity

Hepatocytes exhibit distinct polarity, forming narrow apical tubes (bile canaliculi, BCs) between adjacent cells. These structures essential to liver architecture and function. Unlike most epithelial cells, hepatocytes express both E- and N-cadherin but their functions and mechanisms remain unknown. We show that E- and N-cadherin are collectively required for hepatic polarity and BC formation but act through distinct, spatially segregated pathways. Both localize to adherens junctions; E-cadherin additionally localizes to lateral membranes and the cleavage furrow during cell division, where it promotes BC elongation and new cell-cell contact formation by controlling spindle orientation and RhoA activation via NuMA and ARHGEF17. N-cadherin maintains hepatic polarity by facilitating RhoA inactivation through the p120-catenin family member ARVCF and its partner p190B/ARHGAP5. Thus, dual cadherin expression drives hepatic polarity and BC formation by controlling RhoA activity in a coordinated but opposing manner. SummaryHayase et al. show that E-cadherin promotes bile canaliculi elongation via RhoA activation and oriented cell division, while N-cadherin maintains hepatic polarity by suppressing RhoA, revealing the function and mechanism of dual cadherin expression in hepatocytes.

cell biology↗

bioRxiv2025

Multi-Scale Kinetics Modeling and Advanced Assay for mRNA-Lipid Nanoparticle Potency Assessment

mRNA lipid nanoparticle (mRNA-LNP) technology has attracted global attention, especially in vaccine development, due to its superior delivery efficiency, molecular stability, and safety profile. However, evaluating mRNA-LNP potency--defined as the quantifiable biological response elicited by the product--remains costly and time-consuming when relying solely on in vitro experiments. Rapid and reliable potency assessment is hindered by limited mechanistic understanding of delivery processes and sparse experimental data. To address these challenges, we present a mechanism-informed, multi-scale kinetic modeling framework that quantitatively captures the coupled dynamics across particle-level, cellular, and macroscopic scales. This model incorporates variability in LNP-cell interactions and accounts for critical factors such as dosage, LNP and cell size distributions, and cell proliferation dynamics--all of which influence delivery efficiency and response variability. By integrating advanced multi-omics assays--such as single-molecule fluorescent in situ hybridization (smFISH), which enables single-cell resolution of mRNA and protein expression--our framework leverages heterogeneous, multi-scale data to support mechanistically grounded modeling of mRNA delivery and enable robust predictions of therapeutic potency. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/679406v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1f3ec2borg.highwire.dtl.DTLVardef@1163893org.highwire.dtl.DTLVardef@1dc530borg.highwire.dtl.DTLVardef@1d0264a_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2025

Hyperactivated Glycolysis Drives Spatially-Patterned Kupffer Cell Depletion in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression is characterized by hepatic inflammation and cell death, yet the mechanisms underlying Kupffer cells (KCs) loss remain poorly understood. Here, we sought to elucidate the metabolic basis of KCs death during MASLD. Using metabolomics, immunostaining, and flow cytometry, we evaluated metabolic alterations and KCs death throughout early MASLD progression. We found that KCs death is an early hallmark of MASLD, exhibiting greater susceptibility and displaying a spatial distribution consistent with KCs zonation. Moreoever, KCs undergo progressive metabolic reprogramming toward enhanced glucose utilization during MASLD development, which is correlated with KCs death. In combination of biochemical agonist, isotope tracing and primary KCs culture, we further demonstrated that augmented glycolytic metabolism directly drives KCs death in vitro. Consistently, using Chil1-deficient mice, we further demonstrated that increased glucose utilization accelerates KCs death in vivo. Together, these findings establish a causal link between glycolytic activation and KCs loss during MASLD progression, highlighting glucose metabolic pathways as potential therapeutic targets to preserve KCs homeostasis and mitigate MASLD.

pathology↗