Biology subjects

Xu, Z.

Publications and source records attributed to Xu, Z..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Genetic interaction between Adgrg6 and Sox9 reveals a feedforward mechanism for postnatal spinal stability

Adolescent idiopathic scoliosis (AIS) is the most common spinal disorder in children and is best understood as a complex polygenic condition. Genome-wide association studies (GWAS) have identified several AIS risk loci, including regions near ADGRG6 and SOX9, yet the functional mechanisms underlying AIS heritability remain poorly defined. Here, we use spatial transcriptomics to characterize altered gene expression in the spine of a conditional Adgrg6 mutant mouse model of AIS (Adgrg6-cKO), revealing reduced expression of Sox9 and several components of extracellular matrix organization in the intervertebral disc. We further show that SOX9 occupies regions of open chromatin within the Adgrg6 locus in cells isolated from the mouse intervertebral disc. Finally, we demonstrate a strong genetic interaction between Adgrg6-cKO and a hypomorphic Sox9 allele that increases both the penetrance and severity of AIS-like pathology in mice. Collectively, these findings support a self-reinforcing feedforward regulatory circuit, where Adgrg6 and Sox9 are co-regulated to maintain extracellular matrix gene expression in the annulus fibrosus and paraspinal tissues. These findings provide mechanistic insight into the functional significance of AIS-associated GWAS loci near ADGRG6 and SOX9 and establish combined Adgrg6-Sox9 insufficiency as a tractable model of polygenic scoliosis susceptibility. O_LIAdgrg6 maintains Sox9 and extracellular matrix gene expression in the intervertebral disc C_LIO_LISOX9 directly occupies open chromatin at the Adgrg6 locus in SOX9 skeletal cells C_LIO_LIAdgrg6 and Sox9 genetically interact to increase scoliosis incidence and severity C_LIO_LICombined loss of Adgrg6 and Sox9 drives ectopic cartilage formation and reduced vertebral bone mineral density in the thoracic spine C_LI

developmental biology↗

bioRxiv2026

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

cancer biology↗

bioRxiv2026

Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility

Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process and T cells subjected to chronic antigen exposure have compromised effector function despite high rates of glycolysis. Here we report the ability of the short-chain -hydroxy acid, D--hydroxybutyrate, to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation, even in glucose-replete media. This conversion suppresses both AMPK phosphorylation and the integrated stress response (ISR) in activated T cells while significantly elevating the level of the phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induction of CD8-effector gene transcription was coupled to bioenergetics by enhanced ATP-dependent remodeling of chromatin accessibility at effector gene loci. DAHB enhanced CD8+ T cell antitumor activity both in vitro and in vivo, and DAHB treatment of transferred T cells led to persistent in vivo antitumor effects. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

immunology↗

bioRxiv2026

A Conserved Geometric Code: Extracellular Matrix Curvature Directs Cell Migration Strategy via Nuclear Mechanosensing

Cells navigate complex tissue microenvironments defined by intricate physical cues, yet how they interpret the three-dimensional geometry of the extracellular matrix (ECM) remains an open question. Current models often fail to account for the tortuous architectures found in physiological tissues. Here, we demonstrate that ECM curvature functions as a tissue-specific geometric code read by the cell nucleus. By mapping collagen architectures across cancers and tissues, we find unique curvature fingerprints preserved during metastasis. Using micro-engineered substrates, we show that high curvature imposes localized nuclear bending stress, triggering a Lamin A/C-cPLA2-Ca2+ mechanotransductive cascade. This sensor rewires the cytoskeleton from longitudinal stress fibers to a cortical actomyosin network, driving a sharp transition from fast mesenchymal migration to a slower, exploratory amoeboid phenotype. We term this "nuclear curvotaxis", establishing a physical principle linking static geometry to dynamic strategy, with implications for predicting metastatic risk, understanding immune exclusion, and designing bio-instructive scaffolds for tissue engineering.

biophysics↗

bioRxiv2026

VarDCL: A Multimodal PLM-Enhanced Framework for Missense Variant Effect Prediction via Self-distilled Contrastive Learning

Missense variants are a common type of genetic mutation that can alter the structure and function of proteins, thereby affecting the normal physiological processes of organisms. Accurately distinguishing damaging missense variants from benign ones is of great significance for clinical genetic diagnosis, treatment strategy development, and protein engineering. Here, we propose the VarDCL method, which ingeniously integrates multimodal protein language model embeddings and self-distilled contrastive learning to identify subtle sequence and structural differences before and after protein mutations, thereby accurately predicting pathogenic missense variants. First, leveraging sequence and structural information before and after mutations, VarDCL generates sequence-structural multimodal features via different language models. It incorporates both global and local perspectives of feature embeddings to provide the model with dynamic, multimodal, and multi-view input data. Additionally, a Self-distilled Contrastive Learning (SDCL) module was proposed to enable more effective information integration and feature learning, enhancing the models ability to detect sequence and structural changes induced by mutations. Within this module, the multi-level contrastive learning framework excels at capturing information differences before and after mutations within the same modality; meanwhile, the feature self-distillation mechanism effectively utilizes high-level fused features to guide the learning of low-level differential features, facilitating information interaction across different modalities. The VarDCL framework not only ensures the models capacity to learn dynamic changes pre- and post-mutation but also significantly improves cross-modal information interaction between sequence and structure, thereby remarkably boosting the models performance in distinguishing pathogenic mutations from benign ones. To validate the effectiveness of VarDCL, extensive experiments were conducted. The ablation study demonstrates that all key components of VarDCL contribute significantly. On an independent test set containing 18,731 clinical variants, VarDCL achieved an AUC of 0.917, an AUPR of 0.876, an MCC of 0.690, and an F1-score of 0.789, outperforming 21 state-of-the-art existing methods. Benchmark analysis shows that VarDCL can be utilized as an accurate and potent tool for predicting missense variant effects.

bioinformatics↗

bioRxiv2026

HMA proteins produce 2',3'-cNMP signaling molecules and activate CNL-mediated immunity in rice

Plants deploy a sensor repertoire, usually NLRs, to perceive pathogen effectors and activate executor NLR-triggered immunity. Here we reveal that rice HMA proteins function as sensors detecting the Magnaporthe oryzae MAX effector AvrPigm to trigger broad-spectrum blast resistance mediated by the CNL PigmR. AvrPigm is conserved with multiple copies in blast genomes and targets HMA proteins, facilitating HMA translocation into the cytoplasm. Cryo-EM structure of the HPP04HMA reveals a filament-like oligomer with ssDNA/RNA bound inside the filament, which display cyclic nucleotide synthase activity to generate 2',3'-cNMP in a CNL-dependent manner. We further discovered that the LRR domains of the executor CNLs perceive 2',3'-cNMP to mount immunity. Our study thus establishes an unrecognized immunity mode with a distinct repertoire of sensor receptors that produce signaling molecules that are perceived by the LRR domains of executor NLRs to mediate immunity, shedding new light on the sensor-executor conception and immune activation in plants. HighlightsO_LIHMA proteins and CNL receptors form a new sensor-executor mode in plant immunity C_LIO_LICryo-EM reveals the filament-like structure of HMA-ssRNA/ssDNA C_LIO_LIHMA proteins are cyclic nucleotide synthetases to generate 2',3'-cNMP C_LIO_LILRR domains of CNLs perceive 2',3'-cNMP to mediate immunity C_LI

plant biology↗

bioRxiv2026

Telomere-to-telomere gap-free genome assembly integrated with multi-omics uncovers shading mediated regulation of leaf aroma biosynthesis in aromatic crop Pandanus amaryllifolius

Pandanus amaryllifolius is a valuable aromatic crop widely cultivated in tropical forest understories. Here, A telomere-to-telomere, gap-free genome assembly of the Chinese cultivar Taishan Banlan was generated, and the molecular basis underlying shading-mediated regulation of leaf aroma biosynthesis was elucidated for the first time through integrated genomic, transcriptomic, and metabolomic analyses. Volatile metabolomics identified 1599 volatile organic compounds in leaf tissue, with terpenoids as the primary contributors to leaf aroma. Shading modulated the aroma quality of P. amaryllifolius primarily via terpenoid biosynthesis, yielding aroma profiles dominated by sweet, fruity, green, and woody notes. Integrated transcriptomic profiling revealed that terpenoid biosynthesis is co-regulated by structural genes in the MVA/MEP pathways, TPS family members, and key transcription factors, which collectively modulate the biosynthesis and accumulation of the three core differential terpenoids. Our findings provide valuable resources for the targeted genetic improvement and efficient cultivation optimization of P. amaryllifolius.

genomics↗

bioRxiv2026

Synaptic Input Triggers On-Demand Spine-Specific Mitochondrial ATP Production and Delivery

Synaptic activity imposes acute energy demands, especially for restoring ionic gradients via pumps and exchangers that require ATP. While mitochondria are positioned near dendritic spines to meet this demand, how ATP is produced and delivered with spatial precision remains unclear. Here, using high-resolution calcium and ATP imaging, immuno-cytochemistry, and computational modeling, we demonstrate that synaptic input--but not back-propagating action potentials (bAPs)--triggers on-demand mitochondrial ATP production. This occurs only in spines containing a spine apparatus (SA), where calcium-induced calcium release (CICR) activates mitochondrial calcium uniporters (MCUs), initiating ATP synthesis. We show that ATP delivery is spatially constrained to mitochondrial regions facing the spine base, where ATP-synthase is enriched. Importantly, ATP produced elsewhere on the mitochondrial surface tends to diffuse into the dendrite. We further demonstrate that the delivery of ATP to the spine head is geometrically optimized: an intermediate spine neck length maximizes delivery efficiency. Mathematical modeling and simulations revealb that the time scale for ATP to reach and refill all head-localized exchangers is on the order of hundreds of milliseconds--fast enough to meet local metabolic needs. The present findings establish a mechanism in which nanoscale calcium signaling and mitochondrial architecture together ensure rapid, spatially targeted ATP delivery, tightly coupled to synaptic activity.

neuroscience↗

bioRxiv2026

Integrated Modeling of BCR/TCR Repertoire Diversity Reveals the Mechanistic Basis of Immune Imprinting and Chronic Infection Control

The adaptive immune system orchestrates a complex interplay between humoral and cellular responses to resolve pathogen invasion and suppress tumorigenesis [1,91]. However, a unified quantitative framework integrating lymphocyte repertoire diversity with system-level kinetics remains elusive. Here, we present a multi-scale mathematical model that explicitly incorporates B-cell receptor (BCR) and T-cell receptor (TCR) clonotypic diversity into a discrete agent-based simulation. This framework mechanistically elucidates pivotal immunological phenomena, including the affinity-dependent selection in germinal centers [25], the kinetic constraints of immune imprinting ("original antigenic sin") [54], and the bifurcation between acute and chronic infection trajectories [15,59]. We identify that chronic infections are sustained by specific kinetic thresholds of viral replication relative to antibody affinity maturation. Furthermore, our simulations of cancer-immune interactions demonstrate that therapeutic efficacy is non-linearly dependent on neoantigen presentation [78] and T-cell exhaustion thresholds [79]. This work bridges the gap between reductionist data and systems biology, providing a "quantitative immunology" platform to optimize vaccine dosing schedules and design precision immunotherapies.

immunology↗

bioRxiv2026

Faf2/Ubx2 potentiates p97/Cdc48 segregase activity via functional priming and reinforcement of the UT3 domain in Ufd1

The AAA+ segregase p97/Cdc48 extracts poly-ubiquitinated proteins from entrenched cellular environments to maintain proteostasis. However, its functional capacity is not uniform; extracting substrates from dense assemblies like stress granules or membrane necessitates a fully potentiated state. Here, using precisely synthesized ubiquitinated substrates, we show that the Faf2/Ubx2 cofactor hyperactivates p97/Cdc48, lowering its minimal ubiquitin chain requirement and broadening linkage specificity. Cryo-EM analysis of the activated complex demonstrates that Faf2/Ubx2 potentiates p97/Cdc48 segregase activity by structurally remodeling the substrate recognition module (K48-diUbProx) and priming its engagement with the AAA+ motor (p97/Cdc48-Npl4). These coordinated actions establish a pump-unit architecture that drives efficient substrate processing. Our findings illuminate a conserved mechanism that unlocks the maximal capacity of p97/Cdc48 and provide a blueprint for therapeutically targeting its hyper-activated state in disease.

biochemistry↗

bioRxiv2026

Metabolic exchange and siderophore sharing underlie emergent biofilm synergism

Biofilm communities exhibit emergent properties that exceed the sum of contributions from individual members of the community. Here, we describe a multilayered metabolic interaction that drives enhanced biofilm formation among three bacterial species from the plant rhizosphere. Comparative metatranscriptomic and metabolomic analyses reveal that Bacillus velezensis-secreted 5-aminovaleric acid promotes the growth of the other community members, Burkholderia contaminans and Acinetobacter baumannii. In return, B. contaminans supplies branched-chain amino acids for B. velezensis. Branched-chain amino acids and cell-cell signaling acyl-homoserine lactones from B. contaminans induce biosynthesis of the siderophore bacillibactin in B. velezensis, that is further enhanced by A. baumannii. In exchange, the B. velezensis-secreted siderophore promotes the growth of B. contaminans in iron-limited conditions, which benefits the multispecies biofilm community in vitro and promotes plant growth performance in iron-depleted soil. Our study reveals the molecular mechanisms underlying an emergent rhizosphere biofilm community function and demonstrates its importance in plant-microbe interactions.

microbiology↗

bioRxiv2026

Transplanting ANXA1- CD8+ Naive T cells Delay Aging Through Senolysis

Immunosenescence is a hallmark of aging, yet strategies using defined immune subsets to counteract it are largely unexplored. We performed paired scRNA/TCR-seq on CD45 cells from human bone marrow (15 donors, 3-91 years). T cells were the most altered lineage, with CD8 naive T cell contraction and functional impairment. We identified an expanding ANXA1 CD8 naive subset with senescence signatures and impaired function. ANXA1-deficient CD8 T cells exhibited increased resting stemness and enhanced activation/cytotoxicity upon stimulation. ANXA1- cells showed senolytic activity in vitro and reduced senescence burden in vivo. Monthly transfer of syngeneic ANXA1- CD8 naive T cells into aged mice extended median lifespan by >30 weeks, improving cardiac function, bone density, motor coordination, and marrow immune microenvironment. Our study identifies ANXA1 as critical in CD8 naive T cell aging and establishes ANXA1- cell transfer as a strategy to counter immunosenescence and promote healthy aging.

immunology↗

bioRxiv2026

CLM-X: A multimodal single-cell foundation model with flexible multi-way Transformer for unified scRNA-seq and scATAC-seq analysis

AO_SCPLOWBSTRACTC_SCPLOWAdvances in single-cell multimodal profiling have enabled a more systematic analysis of cellular biology, yet the rapid accumulation of large-scale, heterogeneous datasets poses substantial challenges for integrative analysis. Recently, Transformer-based cell language models (CLMs) are becoming powerful foundational tools for learning transferable cell representations from unimodal single-cell datasets. However, a unified and flexible multimodal foundation model for joint modeling of scRNA-seq and scATAC-seq datasets remains underexplored. Here, we present CLM-X, a multimodal single-cell foundation model built on multiway Transformer architecture. CLM-X employs a harmonized tokenization design together with a stage-wise masked reconstruction pretraining strategy, enabling unified modeling of RNA-only, ATAC-only, and paired RNA-ATAC input within a single Transformer-based framework. We pretrain CLM-X on million-scale unimodal and multimodal datasets, and systematically evaluate its transferability on five downstream tasks including batch correction, modality integration, cross-modal translation, cell type annotation, and perturbation prediction. Across comprehensive benchmarks on 10 datasets, CLM-X consistently outperforms existing multimodal methods and unimodal foundation models, with particularly clear advantages in RNA-ATAC cross-modal translation and genetic-perturbation-response prediction. Overall, CLM-X establishes a unified and flexible multimodal foundation model for integrative analysis of scRNA-seq and scATAC-seq datasets, advancing a more robust, comprehensive, and biological interpretable single-cell analysis beyond current multimodal fusion approaches and unimodal foundation models.

genomics↗

bioRxiv2026

3D, multi-omic imaging reveals molecular biomarkers of the pre-metastatic niche in lung cancer

The recurrence rate following complete surgical resection of primary non-small cell lung cancer is as high as 55%, yet no approach currently exists to evaluate the risk of local recurrence. The premetastatic paradigm is the recognition that metastasis is preceded by reprogramming naive tissues to prime a microenvironment for tumor cell survival and subsequent reactivation. Identification of biomarkers of the pre-metastatic niche would allow us to evaluate a patients risk of local relapse in the normal lung parenchyma surrounding the resected tumor. We designed a workflow incorporating in vivo modelling, radiology, and deep learning-guided three-dimensional (3D) imaging, spatial proteomics, and transcriptomics to identify previously unreported signals associated with the early transformation of the lung parenchyma announcing regional metastasis. We curated biorepository spanning timepoints before and after resection of primary Lewis Lung Carcinoma (LLC) tumors. Using radiology and cellular resolution 3D histology, we calculated the number and distribution of metastases in mouse lungs and developed an algorithm to guide placement of spatial proteomics and transcriptomics to regions containing early micro-metastases and the pre-metastatic microenvironment. Molecular and tissue features associated with presence, size, and location of metastases guided the identification of both myeloid (F4/80) and senescent (p16/p21) cell signatures in the premetastatic and metastatic environments. Finally, multiparametric flow cytometry of metastatic lungs in a senescence reporter GEMM (tdTomato-p16 INKA mice) resolved senescent cells including alveolar macrophages as the cellular phenotypes associated with these early premetastatic signatures. Altogether, this work highlights a novel AI-assisted approach for detection of biomarkers of tissue remodeling during lung cancer invasion.

bioengineering↗

bioRxiv2026

Non-enzymatic ABHD6 interacts with Akt-FoxO1 axis to regulate selective hepatic insulin resistance

The enzymatic function of ABHD6 on insulin secretion and insulin resistance is well documented. However, its non-enzymatic function, especially its effects on selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD) is completely unexplored. ABHD6 is elevated under conditions of diet-induced obesity and aging. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver specific overexpression of native and enzymatic inactive mutant ABHD6 mouse models. We demonstrated that ABHD6 is an unidentified regulator of selective hepatic insulin resistance and contributes to MASLD and liver fibrosis. Furthermore, we found that non-enzymatic ABHD6, rather than its enzymatic form, contributes to this regulation. Mechanistically, we found that ABHD6 translocated into the nucleus and interacted with Akt/FoxO1 axis to regulate its function. In addition, knockdown of FoxO1 in primary hepatocytes or overexpression of constitutively active mutant FoxO1 by AAV approach could completely abolish the effects of ABHD6 on glucose tolerance and gluconeogenesis. Our study reveals an entirely different mechanism underlying selective hepatic insulin resistance that involves a previously unknown non-enzymatic function of ABHD6. This study opens an avenue for the development of a novel class of ABHD6 inhibitors to treat MASLD and liver fibrosis. HighlightsO_LIABHD6 expression in the liver is increased with obesity and aging. C_LIO_LIABHD6 manipulation affects selective hepatic insulin resistance, MASLD and liver fibrosis. C_LIO_LINon-enzymatic ABHD6 interacts with Akt/FoxO1 axis to regulate FoxO1 transcriptional activity. C_LIO_LIThe effects of ABHD6 on glucose tolerance and hepatic gluconeogenesis are completely dependent on FoxO1 activity. C_LI

physiology↗

bioRxiv2026

Mutant FGFR3 restricts bone yet expands cortex via ERK-mediated self-repression

FGFR3 gain-of-function mutations cause achondroplasia 1,2, the most common form of dwarfism, yet trigger paradoxical cerebral overgrowth and skeletal stunting 3-9. Here, we demonstrate that Fgfr3-K644E mutant drives enhanced ERK activation, which then represses Fgfr3 expression and downregulates ERK signaling. In the developing cortex, this mechanism transiently expands cortical stem cells by activating ERK, then shifts signaling to downregulate Fgfr3/ERK/PKA and enhance YAP/TAZ, promoting cerebral overgrowth and premature ependymal maturation. In growing bones, Fgfr3-K644E mutant first elevates ERK to inhibit chondrocyte pre-hypertrophy, then downregulates Fgfr3/ERK/PKA and upregulates YAP/TAZ to accelerate premature hypertrophy and ossification. Our findings establish that FGFR3 mutations limit bone yet expand cortical size via an ERK negative feedback loop, revealing a unified disease mechanism and novel therapeutic targets.

developmental biology↗

bioRxiv2026

MtDNA heteroplasmy controls tumor immune reprogramming through mitochondrial translation

Mitochondrial DNA (mtDNA) mutations are among the most frequent genetic alterations in human cancers, yet their molecular mechanisms in shaping tumor progression and metastasis under physiological conditions remain poorly understood. Here, we show that mtDNA heteroplasmy acts as a tumor cell-intrinsic rheostat that orchestrates fate decisions between progression and suppression. Moderate heteroplasmy induces a ribosomal storm of mitochondrial translation and ribosome biogenesis, driven by leucyl-tRNA synthetase 2 (LARS2). This response enhances metabolic fitness and licenses the secretion of S100A8/A9, enabling tumor cells to actively remodel the immune microenvironment through recruitment of myeloid-derived suppressor cells and exclusion of CD8 T cells, thereby promoting immune evasion and metastatic progression. In contrast, high heteroplasmy impairs tumorigenesis due to oxidative phosphorylation collapse. Disruption of LARS2, mitochondrial translation, or S100A9 signalling abrogates tumor progression. Our findings establish mtDNA heteroplasmy as a key regulator of cancer evolution, linking mitochondrial genetic variation to immune modulation, and reveal the LARS2-mitochondrial translation-S100A8/A9 axis as a therapeutically targetable programme within the pro-tumorigenic window of mtDNA heteroplasmy.

cancer biology↗

bioRxiv2026

Targeting Circulating FABP4 Ameliorates Obesity-Associated Hepatic Steatosis

Obesity is a major driver of hepatic steatosis, yet the molecular link between excess adiposity and hepatocellular lipid accumulation remains incompletely defined. Here, we identify circulating fatty acid-binding protein 4 (FABP4) as a key mediator of adipocyte-hepatocyte lipid crosstalk in obesity. Analyses of human liver specimens and mouse models reveal aberrant accumulation of FABP4 protein--but not transcript--in hepatocytes during steatosis, indicating an extrinsic source. Genetic deletion of FABP4, specifically in adipocytes, protects against high fat diet-induced hepatic steatosis without altering obesity or systemic lipid levels. Mechanistically, circulating FABP4 directly binds to hepatocytes, facilitating free fatty acid uptake. Furthermore, we developed a high-affinity humanized monoclonal antibody that selectively neutralizes circulating FABP4, blocks hepatocyte binding, suppresses fatty acid uptake, and markedly attenuates hepatic steatosis in multiple obese mouse models. These findings establish circulating FABP4 as a pathogenic lipid chaperone and a promising therapeutic target for obesity-associated hepatic steatosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/701451v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@5b91d5org.highwire.dtl.DTLVardef@1c34892org.highwire.dtl.DTLVardef@1d17ea9org.highwire.dtl.DTLVardef@d2b43c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHepatocytic accumulation of extrinsic FABP4 links adiposity to liver lipid deposition. C_LIO_LISpecific deletion of FABP4 in adipocytes prevents hepatic steatosis without affecting systemic lipid levels or obesity. C_LIO_LICirculating FABP4 derived from adipocytes directly binds hepatocytes to facilitate free fatty acid transfer. C_LIO_LIBlocking circulating FABP4 with a high-affinity anti-FABP4 monoclonal antibody inhibits hepatocyte lipid uptake and attenuates steatosis in multiple obese mouse models. C_LI

pathology↗