Biology subjects

Zhao, X.

Publications and source records attributed to Zhao, X..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Ferrapoptosis: Discovery of a Hybrid Programmed Cell Death

Traditional taxonomies classify ferroptosis and apoptosis as distinct forms of regulated cell death. Here, we challenge this view by defining and validating a previously unrecognized neuronal death entity in traumatic brain injury (TBI), which we term "Ferrapoptosis". This hybrid mode of death is characterized by the coexistence of ferroptotic and apoptotic molecular and ultrastructural features within the same neuron-- ultrastructural alterations that cannot be fully characterized by any known cell death modalities. By integrating single-cell transcriptomics with multi-layered functional assays, we show that Ferrapoptosis dominates in severe injury and the acute phase, and is critically driven by mitochondrial oxidative stress. Over time, its predominance is gradually replaced by death modes in which either ferroptosis or apoptosis alone becomes the major pathway. Genome-wide CRISPR screening further identifies Smg7 as a key regulator that synchronously activates both death programs to drive the hybrid phenotype, whereas genetic or viral inhibition of Smg7 reduces Ferrapoptosis and promotes neurological recovery after TBI in mice. Our work systematically delineates a previously unrecognized form of cell death and its pathogenetic mechanisms, providing experimental evidence to refine cell death classification, and suggesting a conceptual strategy for treating complex diseases such as TBI by targeting shared regulatory nodes. HIGHLIGHTSO_LIDefined and validated a previously unrecognized cell death modality, termed "Ferrapoptosis". C_LIO_LIElucidated the ordered pattern of Ferrapoptosis across key stages of TBI pathogenesis. C_LIO_LIRevealed mitochondrial oxidative stress as the pivotal hub integrating ferroptosis and apoptosis. C_LIO_LIIdentify Smg7 as a core driver of Ferrapoptosis and a promising neuroprotective target. C_LI

cell biology↗

bioRxiv2025

Sex- and ketogenesis-dependent effects of intermittent fasting against diet-induced obesity and fatty liver disease

ABSTRACTSIntermittent fasting (IF) improves metabolic health, yet the requirement for hepatic ketogenesis in mediating these benefits remains unclear. Here, we investigated how hepatic ketogenesis contributes to the metabolic and hepatic effects of IF in male and female mice. In the human liver, ketogenesis-associated genes showed sex-dependent correlations with inflammatory and fibrotic pathways. In mice, fasting increased circulating ketone bodies, with females exhibiting a greater rise, indicating intrinsic sex differences in ketone metabolism. IF reduced body weight and adiposity in both sexes, and these systemic benefits persisted despite antisense oligonucleotide (ASO)-mediated knockdown of hepatic Hmgcs2. In contrast, hepatic benefits were sex- and ketogenesis-dependent. IF markedly reduced steatosis and fibrosis in male mice, but these improvements were attenuated or abolished when hepatic ketogenesis was disrupted. Female mice showed minimal hepatic benefit from IF and displayed heightened susceptibility to steatosis, fibrosis, and inflammatory activation under ketogenic insufficiency. Single-cell transcriptomic analyses identified neutrophils and myofibroblasts as key responders to hepatocyte-derived ketone bodies, and IF suppressed neutrophil-driven inflammatory signaling in a ketogenesis-dependent manner in males but not females. Together, these findings demonstrate that while systemic metabolic improvements from IF are largely ketogenesis-independent, the hepatic anti-steatotic and anti-fibrotic effects of IF are sexually dimorphic and require intact hepatic ketogenesis.

physiology↗

bioRxiv2025

An Enhanced Variant-Aware Deep Learning Model for Individual Gene Expression Prediction

Accurate prediction of gene expression from individual whole-genome sequences is critical for understanding disease mechanisms and advancing precision medicine. Current methods, however, struggle with individual-specific genetic variations and integrating detailed sequence context. To address this, we introduce GenomicVariExpress (GVE), a novel deep learning model that leverages a pre-trained sequence encoder and incorporates an Enhanced Variant Integration Module (EVIM). EVIM explicitly encodes and fuses multi-dimensional variant features, such as type, allele frequency, and predicted functional impact, enabling GVE to precisely capture how individual variations modulate gene expression. We evaluate GVE using paired whole-genome and RNA sequencing data from the GTEx Whole Blood cohort. Our experiments demonstrate GVE consistently achieves superior performance compared to state-of-the-art baselines. An ablation study confirms EVIMs critical contribution to this improved performance. Furthermore, analyses highlight GVEs enhanced biological interpretability and its superior performance across multiple tissues and for genes influenced by rare variants. GVE represents a significant step towards accurate, individual-level gene expression prediction, offering a powerful tool for genomic function research and personalized healthcare applications.

bioinformatics↗

bioRxiv2025

Localized control of protein phase separation via membrane binding

Phase separation of protein-rich condensates is key for the spatial organization of cells. Multivalent proteins can phase separate in the bulk cytoplasm to form 3D condensates or at the membrane surface to form 2D condensates. How cells control 2D versus 3D phase transitions is not well understood. Here, we combine an in vitro model system of membrane surface phase separation with thermodynamic modelling to explore the relation of 2D and 3D phase transitions. We engineered the phase-separating protein FUS to bind to membranes and quantified 2D and 3D phase separation as a function of total FUS concentration and salt concentration. We find that membrane binding induces the formation of 2D surface condensates far below the bulk saturation concentration. In addition to direct FUS-membrane binding, surface condensates sequester more FUS molecules from the bulk via protein-protein interactions, resulting in a substantial deviation from the classical binding isotherm. By changing the protein-protein interaction strength via salt titration, we find that the saturation concentrations for 2D and 3D phase separation are coupled. By extending the classical theory of condensate wetting via membrane binding, we recapitulate the experimental results and show that tuning the membrane-binding strength of a phase-separating protein provides a robust way to control 2D condensation at the membrane over a wide concentration range without entering the 3D condensation regime. Taken together, our results provide a simple framework to understand how cells tune protein interactions and membrane binding to control 2D and 3D phase transitions.

biophysics↗

bioRxiv2025

A Study on the Pharmacokinetic/Pharmacodynamic Profiles of the Novel PPAR Pan Agonist Chiglitazar Sodium in Rats with Hypoalbuminemia

ObjectiveTo compare the changes in the pharmacokinetic/pharmacodynamic (PK/PD) profiles of Chiglitazar Sodium between healthy rats and those with hypoalbuminemia, and to evaluate the medication safety of Chiglitazar in rats with hypoalbuminemia. MethodsLiquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method was employed to determine the plasma concentration ofChiglitazar Sodium in both healthy rats and rats with hypoalbuminemia after administration. Pharmacokinetics were calculated based on the measured data. Blood glucose levels were monitored and recorded in both groups to observe pharmacodynamic changes. ResultsPharmacokinetic analysis revealed that, compared to the healthy group, only the Tmax in the hypoalbuminemia group was significantly earlier by 34.3% (P<0.001), while other pharmacokinetic parameters showed no significant differences. Pharmacodynamic studies indicated that blood glucose levels remained stable in both healthy rats and rats with hypoalbuminemia during the 0.25-10 hour monitoring period. ConclusionExcept for Tmax, there were no significant differences in PK/PD parameters between rats with hypoalbuminemia and healthy rats. Blood glucose levels remained stable in both groups after oral administration of Chiglitazar Sodium. The animal experimental results suggest that, under normal conditions, hypoalbuminemia does not affect the pharmacokinetic and pharmacodynamic profiles of Chiglitazar Sodium.

pharmacology and toxicology↗

bioRxiv2025

Patient-Specific Midbrain Organoids with CRISPR Correction Reveal Disease Mechanisms and Enable Therapeutic Evaluation in Neuronopathic Gaucher Disease

Neuronopathic Gaucher disease (nGD) is a lysosomal storage disorder caused by GBA1 mutations, leading to defective acid {beta}-glucosidase (GCase) and accumulation of glycosphingolipid substrates, causing inflammation and neurodegeneration. Patients with nGD manifest severe neurological symptoms, but current animal models fail to fully recapitulate human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells (hiPSCs) of nGD patients with GBA1L444P/P415R and GBA1L444P/RecNcil mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiency, resulting in diminished enzymatic function, accumulation of lipid substrates, widespread transcriptomic changes, and impaired dopaminergic neuron differentiation, mirroring nGD pathology. GBA1 mutation correction mediated by CRISPR/Cas9 restored GCase activity, normalized lipid substrate levels, and rescued dopaminergic neuron function, confirming the causal role of GBA1 mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy with GZ452, a glucosylceramide synthase inhibitor currently under clinical investigation. These treatments either restored GCase activity, reduced lipid substrate accumulation, improved autophagic and lysosomal abnormalities, or ameliorated dysregulated genes involved in neural development. These patient-specific, 3D neural models offer a transformative, physiologically relevant platform for unravelling disease mechanisms and accelerating the discovery of therapies for patients with nGD.

neuroscience↗

bioRxiv2025

A 5'-end based Molecular Marker Enables Identification and Deployment of a Functional Rpi-vnt1.1 Allele for Durable Late Blight Resistance in Potato

Potato (Solanum tuberosum) is a globally important food crop, yet its production is severely threatened by late blight, caused by Phytophthora infestans. Deploying resistance (R) genes in breeding programs offers a sustainable approach for disease management. Rpi-vnt1.1 is a broad-spectrum R gene cloned from wild Solanum species Solanum venturii. Here, we developed a PCR marker targeting the 5'-end extension of Rpi-vnt1.1, which enables efficient and specific detection of the resistant alleles. Screening of advanced breeding lines from the International Potato Center (CIP) identified line C1848, which carries a functional Rpi-vnt1.1 allele. Inoculation assays confirmed C1848 confers strong resistance to P. infestans. Subsequent functional assays, including RNAi-mediated silencing in C1848 and heterologous expression in Nicotiana benthamiana, demonstrated that this resistance is specifically mediated by the Rpi-vnt1.1 allele. This specific marker provides a rapid, low-cost tool for marker-assisted breeding, facilitating the deployment of potato cultivars carrying Rpi-vnt1.1.

plant biology↗

bioRxiv2025

Rete Ovarii Epithelial Cells as an Unappreciated Cell of Origin for Pelvic and Ovarian High-Grade Serous Carcinoma

Over the past two decades, converging clinicopathologic, molecular, and evolutionary evidence has established that pelvic and ovarian high-grade serous carcinoma (HGSC) originates predominantly from tubal-type epithelia rather than the ovarian surface epithelium. Consequently, Fallopian tube secretory epithelial cells are widely recognized as the principal cell of origin for HGSC. However, the female reproductive tract contains additional tubular epithelial networks whose potential contributions to HGSC pathogenesis remain unexplored. Here, we identify the rete ovarii (RO), a complex network of intra- and extra-ovarian tubules located within the ovarian hilus and mesovarium, as an alternative candidate tissue of origin for HGSC. We demonstrate that genetic and genomic alterations in rete ovarii epithelial cells (ROECs) can drive their malignant transformation, giving rise to tumors that closely recapitulate the histologic and molecular characteristics of human HGSC. Spatially resolved single-cell transcriptomic analyses of tumors derived from Brca/Trp53/Pten-deficient ROECs (BTP-RO) reveal distinct invasive and immunosuppressive molecular programs. These findings establish ROECs as a previously unrecognized cell of origin for HGSC, expanding the landscape of potential precursor populations beyond the Fallopian tube. The RO-based HGSC model provides a powerful framework for developing origin-informed prevention strategies, early detection approaches, and targeted therapeutics.

cancer biology↗

bioRxiv2025

P2RY2 is a purinergic immune checkpoint linking extracellular ATP to immune evasion and adaptive resistance to immunotherapy

Extracellular ATP (eATP) accumulates substantially in the tumor microenvironment (TME) and rises further during immunotherapy. While canonically an immune-activating "danger" signal, eATP also promotes immunosuppression in tumors, thus far largely attributed to its metabolite, adenosine. Here, we identify direct eATP signaling through P2RY2 as a dominant, adenosine-independent mechanism of immune resistance. Specifically, eATP-P2RY2 signaling serves as the primary upstream driver of COX-1/2 upregulation and consequent accumulation of immunosuppressive PGE2 in the TME, uncovering the long-sought TME-specific trigger of pathological COX-PGE2 hyperactivation in solid tumors. Genetic deletion or pharmacologic inhibition of P2RY2 eliminates both baseline and therapy-induced intratumoral PGE2, restores antitumor T cell responses, and reverses resistance to CAR-T, TCR-T, checkpoint blockade, and TIL therapies. Given that persistently elevated eATP is a hallmark of solid tumors, our work reveals a fundamental mechanism by which tumors hijack innate "danger" signaling to establish immune suppression and develop adaptive resistance to immunotherapy. These findings establish P2RY2 as a purinergic immune checkpoint with translational potential for combinatorial cancer immunotherapies. HIGHLIGHTSO_LIeATP in the TME drives baseline and therapy-induced immune evasion via P2RY2 C_LIO_LIeATP-P2RY2 signaling is the primary cause of PGE2 accumulation in the TME C_LIO_LIP2RY2 propels a feedback loop that enforces adaptive resistance to immunotherapies C_LIO_LIP2RY2 blockade reprograms the TME and restores immunotherapy responsiveness C_LI

immunology↗

bioRxiv2025

Dynamic landscapes of gene regulatory networks in early mammalian neurogenesis: Insights into brain evolution and disorder risk

Neurogenesis--the process of generating neurons--is governed by dynamic transcriptional programs that vary across time, brain regions, and cell types, forming regionally specialized neuronal circuits. To understand these dynamics, we constructed a comprehensive gene regulatory network (GRN) resource encompassing 22 neurogenic lineages from human, macaque, and mouse, enabling cross-species and cross-regional comparisons. Leveraging state-of-the-art trajectory analysis and GRN inference, we characterized temporal regulatory dynamics and introduced a "dynamic score" to identify key subnetworks with lineage-specific dynamics, including hundreds of regulons and co-regulatory modules. Our analysis uncovered both known and novel candidate regulators driving neuronal differentiation and regional identity, spanning the entire human brain, as well as evolutionary divergence in neurogenic GRNs distinguishing human brains. Mapping risk genes to the resource helped understand associated early gene regulatory dynamics with 35 neurodevelopmental disorders and traits including autism, schizophrenia, severe intellectual disability, and microcephaly. This resource is publicly available as an interactive online platform.

developmental biology↗

bioRxiv2025

A matrix-mimicking bioadhesive epicardium for tunable modulation of biomechanics in the acutely infarcted heart

Mitigating adverse tissue remodeling after a heart attack or myocardial infarction (MI) is critical to prevent the development of heart failure. Among various post-MI treatment strategies, mechanical reinforcement of the infarcted region with epicardial patches has promise due to its consistent improvement of chronic cardiac function and its drug- or biologic-free nature. However, despite the variety of patch materials studied to date, the lack of a programmable platform that predictably modifies early-stage cardiac biomechanics to different degrees has prevented further optimization of this strategy. Here, we introduce the matrix-mimicking bioadhesive epicardium (MMBE), a platform that can be rationally designed to achieve a wide range of anisotropic mechanical properties to offer quantifiable mechanical reinforcement of the heart upon application. The platform synergistically combines fully programmable direct-ink-writing of extracellular matrix-inspired crimped fibers and a bioadhesive for sutureless integration to the epicardium. The MMBE platform achieves an array of matrix-mimicking mechanical properties and acute modulation of cardiac biomechanics using numerical analysis, in silico studies and experimental characterizations. Furthermore, the feasibility of the MMBE platform in an in vivo rat model of MI is demonstrated. The MMBE platform can be used to systematically identify patch design parameters that alter post-MI remodeling without introducing confounding biological variables.

bioengineering↗

bioRxiv2025

Label-free biochemical imaging and timepoint analysis of neural organoids via deep learning-enhanced Raman microspectroscopy

Three-dimensional organoids have emerged as powerful models for studying human development, disease and drug response in vitro. Yet, their analysis remains constrained by standard imaging and characterisation techniques, which are invasive, require exogenous labelling and offer limited multiplexing. Here, we present a non-invasive, label-free imaging platform that integrates Raman microspectroscopy with deep learning-based hyperspectral unmixing for unsupervised, spatially resolved biochemical analysis of neural organoids. Our approach enables high-resolution mapping of cellular and subcellular structures in both cryosectioned and intact organoids, achieving improved imaging accuracy and robustness compared to conventional methods for hyperspectral analysis. Using our platform, we demonstrate volumetric imaging of a neural rosette within a neural organoid, and interrogate changes in biochemical composition during early developmental stages in intact neural organoids, revealing spatiotemporal variations in lipids, proteins and nucleic acids. This work establishes a versatile framework for high-content, label-free (bio)chemical phenotyping with broad applications in organoid research and beyond.

bioinformatics↗

bioRxiv2025

Investigation of region-specific effects of pepsin-digested decellularized meniscus on human adipose-derived stromal cells within alginate hydrogels

Meniscus tears are one of the most common musculoskeletal injuries, but treatment options remain limited. The meniscus can be divided into distinct inner and outer regions based on differences in the tissue structure and composition. Recognizing that the extracellular matrix (ECM) provides cell-instructive cues that can direct cell differentiation, the current study investigated the effects of incorporating region-specific ECM derived from decellularized meniscus on the viability, growth, and lineage-specific differentiation of human adipose-derived stromal cells (ASCs) encapsulated in alginate beads. The first phase of research focused on validating a novel decellularization protocol for porcine meniscus, which demonstrated the effective removal of cellular content while preserving key ECM constituents including glycosaminoglycans (GAGs) in both the inner and outer meniscus regions. Subsequently, the decellularized inner meniscus (DIM) and decellularized outer meniscus (DOM) were digested with pepsin and combined with a propriety alginate formulation to enable rapid cell encapsulation under mild conditions. Viability staining confirmed that encapsulated human ASCs remained highly viable over 28 days in culture in proliferation or chondrogenic differentiation media. Under both media conditions, the ASC density was significantly higher in the alginate beads incorporating DIM or DOM as compared to alginate alone controls at 28 days. In addition, gene expression analysis and immunofluorescence staining supported that the incorporation of the pepsin-digested ECM within the alginate enhanced fibrochondrogenic marker expression in the samples cultured in chondrogenic differentiation medium. Qualitatively, more intense staining for collagen types I and II were observed within the beads incorporating DOM as compared to DIM, supporting that the formulations had varying effects. Overall, these studies provide new insight supporting that region-specific meniscus ECM can be harnessed to direct cell phenotype and function towards the goal of developing tissue-specific bioinks for tissue-engineering applications.

bioengineering↗

bioRxiv2025

Uncovering genetic architecture of the heart via genetic association studies of unsupervised deep learning derived endophenotypes

Recent genome-wide association studies (GWAS) have effectively linked genetic variants to quantitative traits derived from time-series cardiac magnetic resonance imaging, revealing insights into cardiac morphology and function. Deep learning approach generally requires extensive supervised training on manually annotated data. In this study, we developed a novel framework using a 3D U-architecture autoencoder (cineMAE) to learn deep image phenotypes from cardiac magnetic resonance (CMR) imaging for genetic discovery, focusing on long-axis two-chamber and four-chamber views. We trained a masked autoencoder to develop Unsupervised Derived Image Phenotypes for heart (Heart-UDIPs). These representations were found to be informative to indicate various heart-specific phenotypes (e.g., left ventricular hypertrophy) and diseases (e.g., hypertrophic cardiomyopathy). GWAS on Heart UDIP identified 323 lead SNP and 628 SNP-prioritized genes, which exceeded previous methods. The genes identified by method described herein, exhibited significant associations with cardiac function and showed substantial enrichment in pathways related to cardiac disorders. These results underscore the utility of our Heart-UDIP approach in enhancing the discovery potential for genetic associations, without the need for clinically defined phenotypes or manual annotations.

bioinformatics↗

bioRxiv2025

Embryonic Atrial Injury Programs an Anti-Fibrotic Atrial Fibrillation Substrate

Atrial myopathy is associated with atrial fibrillation in adults, yet the role of embryonic atrial injury in predisposing individuals to atrial fibrillation remains unclear. Using an inducible, cardiomyocyte-specific diphtheria toxin A-mediated injury mouse model, we found that injured embryonic atria exhibited upregulation of apoptosis and TNF signaling pathways, alongside downregulation of calcium handling and atrial fibrillation-associated genes. Single-cell RNA sequencing revealed two distinct cardiomyocyte populations with differential injury responses. Importantly, although myofibroblasts increased in the fibroblast population, these cells displayed an extracellular matrix gene expression profile distinct from the pro-fibrotic phenotype typically observed in fibrillating adult atria and showed no evidence of fibrosis. Concurrently, monocytes/macrophages were activated and showed upregulated expression of the anti-fibrotic factor GPNMB. These findings suggest that adaptive tissue remodeling is counterintuitively prevented from progressing to fibrosis, potentially through GPNMB-mediated mechanisms. This study elucidates molecular pathways linking developmental atrial injury to myopathy and proposes novel strategies to attenuate atrial fibrillation progression.

pathology↗

bioRxiv2025

Capturing global pet dog gut microbial diversity and hundreds of near-finished bacterial genomes by using long-read metagenomics in a Shanghai cohort

Pet dogs are considered part of the family, and understanding their gut microbiomes can provide insights into both animal and household health. Most comprehensive studies, however, relied on short-read sequencing, resulting in fragmented MAGs that miss mobile elements, antimicrobial-resistance genes, and ribosomal genes. Here, we applied deep long-read metagenomics (polished with short-reads) to fecal samples from 51 urban pet dogs in Shanghai, generating 2,676 MAGs--representing 320 bacterial species--, of which [~]72% achieved near-finished quality, often improving on the corresponding reference public genome. Comparisons with external datasets showed that our Shanghai-based MAG catalog is representative of pet dogs worldwide (median read mapping of >90%). Moreover, we recovered circular extrachromosomal elements, including those linked to antimicrobial resistance, which were also detected in external dog gut datasets. In conclusion, we provide a high-quality reference resource and demonstrate the power of deep long-read metagenomics to resolve microbial diversity in complex host-associated microbiomes.

microbiology↗

bioRxiv2025

ATF4 alleviates doxorubicin-induced cardiomyopathy through H2S-mediated antioxidation

BackgroundDoxorubicin (DOX) remains a cornerstone in the treatment of various cancers. However, its clinical utilization is significantly hampered by dose-dependent cardiotoxicity. The generation of reactive oxygen species (ROS) constitutes the central component of the pathogenesis of DOX-induced cardiotoxicity. Activating transcription factor 4 (ATF4) has been demonstrated to exert a cardioprotective effect and augment cardiac antioxidative capacity in settings of heart failure. However, the role of ATF4 in DOX-induced cardiomyopathy (DIC) remains unknown. MethodsTo explore the role of ATF4 in DOX-induced cardiomyopathy, cardiac-specific ATF4 conditional heterozygous mice and AAV9 mediated ATF4 overexpression mouse models were utilized. Cardiac function was assessed by echocardiography. The upstream regulator and downstream mediator of ATF4 were evaluated using RNA-seq analysis and further verified using ChIP assay and luciferase reporter assay. ResultsWe found a substantial decrease in ATF4 expression levels in the heart of DIC mice. ATF4+/- mice exhibited a higher degree of susceptibility to DOX-induced cardiotoxicity in comparison with ATF4flox/flox mice, as evidenced by the manifestation of more severe cardiac dysfunction and a significantly earlier mortality rate. In contrast, cardiacc-specific overexpression ATF4 by AAV9 confers robust cardioprotection against DOX-induced cardiomyopathy. Mechanistically, we identified the upstream regulator of ATF4 as KLF16, which was significantly suppressed during DOX treatment. Further, the decrease of ATF4 led to a reduction in cystathionine {gamma}-lyase (CSE) transcription and hydrogen sulfide (H2S) production in the context of DOX-induced cardiotoxicity. ChIP and luciferase reporter assays revealed that ATF4 functioned as the transcription factor of the CSE gene, which is a key enzyme in the synthesis of H2S to counteract oxidative stress. Consistently, ROS scavengers or H2S donors was shown to mitigate the consequences of ATF4 deficiency. In contrast, the ectopic expression of ATF4 mitigated oxidative stress and apoptosis in DOX-induced cardiotoxicity, both in vivo and in vitro. ConclusionsOur study revealed a novel function of ATF4 in counteracting oxidative stress in DOX cardiotoxicity by promoting the transcription of CSE. ATF4 may represent a promising therapeutic target for the treatment of DOX-induced cardiomyopathy.

pathology↗

bioRxiv2025

Metabolic Immunosuppression Mediated by Proliferative CD168+TAMs in Colon Cancer

The role of non-monocyte-derived, in situ proliferating tumor associated macrophages (TAMs) in tumor progression has been underappreciated. Proliferative TAM subsets likely represent critical mediators in establishing the immunosuppressive microenvironment, given the susceptibility of TAMs to be hijacked by malignant cells for pro-tumorigenic functions. However, the regulatory networks governing their self-renewal circuitry and lineage bifurcation remained undefined. Combining single cell RNA sequencing of human and murine colon tumors, we identified CD168+ TAMs, a hyperproliferative subpopulation with FOXM1-dependent maintenance of replicative competence. Spatial multi-omics and functional validation revealed that this subset exhibited peritumoral localization and underwent immunosuppressive polarization through cholesterol-coordinated CX3CL1-CX3CR1 signaling. Colon cancer-specific lipid metabolic rewiring elevates glycerophospholipid and cholesterol flux, with PLA2G7-mediated glycerophospholipid catabolism promoting CX3CR1 expression in TAMs. Thus, the CX3CR1 signaling-driven immunosuppressive effect of CD168+ TAM is an integrated response to tumor-specific metabolic features. Targeting the CD168+ TAMs may enable therapeutic strategies for metabolic-immune reshaping in colon cancers.

cancer biology↗