Biology subjects

Zeng, H.

Publications and source records attributed to Zeng, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Genome-scale functional mapping of the mammalian whole brain with in vivo Perturb-seq

Functional genomics studies have provided critical insights into cell type-specific gene regulatory programs, but to date most have been conducted in wild-type tissues or cell cultures. Here, we present a gene expression functional atlas across the mouse brain. We use an enhanced in vivo Perturb-seq platform to analyze transcriptome-wide responses to loss of 1,947 disease-associated genes, profiling over 7.7 million cells spanning major brain regions and neuronal populations. We find striking cell-type-specific essentiality and transcriptional programs and show that closely related disease genes such as two NMDA receptor subunits can drive opposing transcriptional programs. Together, this work reveals insights into the genetics and mechanisms of neurodevelopmental, psychiatric, and neurodegenerative diseases in vivo, paving the way for the design of future genetic medicine.

genomics↗

bioRxiv2026

FishMamba-1: A Linear-Complexity Foundation Model for Deciphering Polyploid Cyprinid Genomes

The Cypriniformes order, comprising essential aquaculture species like carps and minnows, presents unique genomic challenges due to complex whole-genome duplication (WGD) events and extensive repetitive elements. Conventional annotation tools and Transformer-based foundation models often struggle to capture long-range dependencies in these expanded genomes due to quadratic computational complexity. Here, we introduce FishMamba-1, the first genomic foundation model tailored for the aquatic clade, built upon the selective state-space model (SSM) architecture. By leveraging Mamba-2s linear scaling efficiency, FishMamba-1 processes context windows of 32,768 base pairs (32k)--significantly surpassing the 4-6k limit of standard DNA Transformers--enabling the modeling of distal regulatory patterns on a single GPU. We curated Cypri-24, a comprehensive dataset comprising 28.8 Gb of high-quality genome assemblies from 24 representative species, to pre-train FishMamba-1 on 15 billion tokens. Subsequent fine-tuning for genome segmentation (FishSegmenter) demonstrates the models capability to annotate gene structures at single-nucleotide resolution with remarkable precision. Evaluation on a held-out test set reveals that FishMamba-1 achieves a precision of 64.6% in exon identification, effectively distinguishing coding regions from the vast non-coding background without relying on RNA-seq evidence. Furthermore, interpretability analysis confirms that the model captures biological syntax such as splice acceptor motifs. FishMamba-1 provides a scalable, open-source framework for decoding the complex genomes of non-model organisms, providing a scalable computational resource to support downstream applications in molecular breeding and ecological monitoring. The complete source code, pre-trained model weights, and datasets are freely available at https://github.com/lu1000001/FishMamba. Additionally, the FishMamba Hub, a web-based inference platform, is accessible at https://huggingface.co/spaces/lu1000001/FishMamba-Hub to facilitate real-time genomic segmentation for the aquatic research community. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/710409v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@f5ee02org.highwire.dtl.DTLVardef@1dcfd31org.highwire.dtl.DTLVardef@1729ef8org.highwire.dtl.DTLVardef@22e4f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2026

Synthetic Immunological Niche Reveals Early Immune Dysregulationand Stratifies Therapeutic Response in Type 1 Diabetes

In Type 1 Diabetes (T1D), disease onset and response to immunotherapy vary widely among individuals, reflecting heterogeneous stage-specific immune dysregulation that remains undefined. To investigate this heterogeneity, we engineered a microporous polycaprolactone scaffold that forms a synthetic immunological niche (IN) upon subcutaneous implantation, enabling in vivo capture of systemic immune dysregulation. In non-obese diabetic (NOD) mice, longitudinal transcriptomic profiling of IN-infiltrating cells identified early-stage genes relatively enriched for myeloid cells, followed by progressive increases in T cell-associated dysregulation at later stages that distinguished T1D progressors from non-progressors. We derived an early-stage IN-based T1D gene signature capturing immune alterations. The signature stratified NOD progressors from non-progressors as early as 6 weeks of age and was conserved across human T1D datasets, distinguishing T1D from non-diabetic individuals in spleen and pancreatic lymph node samples, but not peripheral blood. Signature-based stratification further revealed enrichment of macrophage-associated TNF- pathways in NOD progressors, validated in human T1D islets. Given heterogeneous response to anti-TNF- therapy, IN profiling identified resistance-associated mechanisms and enabled derivation of a pathway score that prospectively distinguished treatment-sensitive from resistant mice prior to therapy, establishing the IN as a minimally invasive platform for detecting stage-wise immune dysregulation and stratifying immunotherapy response in T1D.

bioengineering↗

bioRxiv2026

MapMyCells: High-performance mapping of unlabeled cell-by-gene data to reference brain taxonomies

Single-cell mapping methods convert raw, heterogeneous single-cell datasets into interpretable and comparable representations of biological identity. As reference cell-type taxonomies mature, mapping new datasets to shared references has become a central strategy for enabling cross-study integration, reproducible annotation, and cumulative biological knowledge. Here we present MapMyCells, an open-source framework designed to align diverse single-cell omics datasets to hierarchical reference taxonomies with minimal preprocessing. MapMyCells provides out-of-the-box support for an expanding set of high-quality brain cell-type references generated by the Allen Institute for Brain Science, the BRAIN Initiative, and the Seattle Alzheimers Disease Brain Cell Atlas, including whole-brain mouse and human atlases, aging and Alzheimers disease cohorts, and a cross-species consensus taxonomy initially focused on the basal ganglia. MapMyCells enables efficient mapping of hundreds of thousands of cells on standard workstations without specialized hardware, providing a deterministic, scalable, and modality-agnostic approach that is robust across species and molecular assays. The framework produces interpretable confidence metrics and quantitative summaries of mapping performance, allowing users to evaluate assignment precision and accuracy. We demonstrate the mapping of unlabeled transcriptomic, epigenomic, and spatial datasets to reference taxonomies and describe a general workflow for preparing arbitrary hierarchical taxonomies for reference-based mapping. As the ecosystem of single-cell reference atlases expands, MapMyCells offers a practical and reproducible solution for community-scale cell-type annotation and cross-dataset integration, supporting the development of unified and extensible brain cell atlases.

bioinformatics↗

bioRxiv2026

SCALPEL: A pipeline for processing large-scale spatial transcriptomics data

Spatial transcriptomics enables the precise mapping of gene expression patterns within tissue architecture, offering unprecedented insights into cellular interactions, tissue heterogeneity, and disease pathology that are unattainable with traditional transcriptomic approaches. We present a tool for processing spatial transcriptomics data, SCALPEL (Spatial Cell Analysis, Labeling, Processing, and Expression Linking). SCALPEL is specifically designed to support the analysis of large, atlas-level datasets. Our new workflow features advanced 3D segmentation optimized for dense and heterogeneous tissues, refined filtering criteria, and transcriptome-based doublet detection to remove low-quality or artifactual cells. Cell type label transfer from existing taxonomies is further improved through updated filtering thresholds. Spatial domain detection is incorporated to capture local transcriptomic organization, and tissue sections are registered to the Allen Mouse Brain Common Coordinate Framework version 3 (CCFv3) for precise anatomical alignment. Genome-wide expression imputation from single-cell RNA-sequencing (scRNAseq) further enriches the dataset. Crucially, we benchmark the performance of this updated pipeline against a previously published version of our whole-mouse-brain (WMB) dataset (Yao et al., 2023b), demonstrating substantial improvements in cell number, expression profile clarity, and spatial registration. These advances provide a robust foundation for downstream spatial analyses and set a new standard for large-scale spatial transcriptomics studies.

bioinformatics↗

bioRxiv2026

Subchondral H-type Blood Vessel Formation Aggravates Articular Cartilage Degeneration through LEP-LEPR Axis

BackgroundOsteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage deterioration that has resulted in severe physical and economic costs for society. Risk factors for osteoarthritis encompass genetic predisposition, mechanical influences, obesity, inflammation, and metabolic problems. Recent reports indicate that the morphological alterations of subchondral bone evolve dynamically with the advancement of osteoarthritis. A significant alteration in subchondral bone is the development of aberrant blood vessels, particularly H-type vessels. H-type arteries are essential for preserving subchondral bone homeostasis. They support nutrients and oxygen to bone tissue and eliminate waste, thereby supporting the metabolic activities of osteoblasts and osteoclasts. However, the upstream factors governing H-type arteries are yet unknown. MethodsThe whole transcriptome analysis was performed by informatics which is further verified in clinical samples. Using LEP and LEPR knockout mice, the correlation between abnormal subchondral bone metabolism and LEP, LEPR, and H-type vessel formation were uncovered. ConclusionsThis study reveals that the lipid metabolism pathway was highly enriched on the OA lesion, and LEP and LEPR were markedly underexpressed in the subchondral bone on the side with severe OA lesions. The causal relationship of the LEP-LEPR-CD31 signalling pathway in aging and osteoarthritis models is revealed at the overall and molecular levels. This project will provide a new theoretical basis for the pathogenesis of early OA and new ideas and targets for the clinical treatment of OA by exploring the LEP-LEPR-CD31 signalling in osteoarthritis.

pathology↗

bioRxiv2025

Absence of MBP 3' UTR in Mice Disrupts mRNA Transport, Myelination, and Motor Learning

Myelin sheath maturation requires compaction, a cellular phenomenon mediated by local translation of myelin basic protein (MBP), which acts as a molecular zipper to join adjacent membranes and extrude the cytoplasm. Contrary to decades-old microinjection experiments indicating that Mbp mRNA transport is restricted to microtubules, we now show using smFISH that endogenous Mbp mRNA granules indeed localize along actin. To validate the in vivo necessity of Mbp mRNA transport and its dependence on the 3 UTR (untranslated region), we replaced the endogenous Mbp 3 UTR with polyA tail sequences. Though these mice have decreased Mbp mRNA levels, this alone could not account for their striking phenotypes - hypomyelination, baseline tremors, and motor learning defects. Thus, we cultured oligodendrocytes from these mice and found defects in both Mbp mRNA localization and local translation. These results demonstrate that the 3 UTR of a locally translated structural protein is critical for both developmental and activity-induced myelination.

cell biology↗

bioRxiv2025

Towards Video-LLM Driven Workflow for Behavioral Segmentation and Scoring in Mice Performing a Skilled Water Reaching Task: An Evaluation of Recent LLM Models

SignificanceBehavior scoring is labor-intensive and subjective, introducing variability in results. Large Language Models (LLMs) capable of video understanding offer a transformative solution to manual scoring, crucial for accelerating and standardizing neuroscience workflows. AimWe sought to benchmark state-of-the-art video LLMs (Gemini 2.5 Pro, Qwen3-VL, and VideoLLaMA3) for automated behavioural segmentation and scoring of mice performing a water-reaching task. ApproachVideos of mice performing water reaching from the front view were analysed by the LLMs. Accuracy was compared across different models and against prompt adjustments within Gemini. To assess classification determinants, video fidelity was altered through pixel interpolation and key regions blurred (paws/snout-mouth). In addition, the models were asked to describe the mouses actions over time. ResultsGemini 2.5 Pro (0.74 {+/-} 0.12 accuracy) and Qwen3-VL-30B (0.67 {+/-} 0.13) exhibited ability to classify trial outcomes. Reliable classification required a minimum pixel resolution of 0.28 mm per pixel. Accuracy is significantly reduced upon obscuring the snout-mouth area. In 549/1058 of videos, Gemini 2.5 Pro also provided completely accurate frame-to-frame behaviour segmentations. ConclusionsVideo-LLMs offer potential to accelerate neuroscience by providing scalable, objective quantification of goal-directed behaviors. By producing temporal annotations, Gemini enables fast first-pass labelling that markedly streamlines manual dataset curation.

neuroscience↗

bioRxiv2025

Spatial patterning of transcriptional and regulatory programs in the primate subcortex

Mammalian brain cell identity is shaped by intrinsic factors and external context. We present a spatially resolved transcriptomic and gene regulatory atlas of cell types across all subcortical regions in a primate, the common marmoset. Dense sampling and cross-species integration revealed spatially precise neuronal assemblies, including in complex midbrain and diencephalic structures. Chromatin accessibility and transcriptional identity are spatially tuned within and across subcortical structures; spatial gradients within hippocampal subfields are orchestrated by graded transcription factors acting through graded enhancers. The primate-expanded thalamic GABAergic population shares transcriptional and regulatory syntax with conserved midbrain populations, reflecting an evolutionary adaptation compared with rodents. Similar regional expression across cell types can arise by distinct regulatory architectures, as for telencephalic astrocytes and neurons. Conversely, distant cell types can share regulatory programs despite divergent identities: striatal GABAergic medium spiny neurons and telencephalic glutamatergic neurons share a postsynaptic regulatory program despite divergent lineage, region, and neurotransmitter identity.

neuroscience↗

bioRxiv2025

Comparative analysis of single-stranded and non-canonical DNA formation in human and other ape cells with telomere-to-telomere genomes

Non-canonical (non-B) DNA secondary structures, e.g., G-quadruplexes and triplex DNA, are mutation hotspots and genome regulators contributing to disease and evolution. Yet they remain uncharacterized in complete genomes in vivo. Here we exploited the fact that many non-B DNA structures form single-stranded DNA (ssDNA). Using permanganate/S1 footprinting across 14 cell lines, we generated ssDNA profiles for human and six non-human ape telomere-to-telomere (T2T) genomes. Newly resolved satellite arrays--e.g., at ribosomal DNA and centromeres--displayed high ssDNA levels, implicating non-B DNA in satellite expansion and function. Hidden Markov Models applied to our ssDNA data revealed active genomic domains with specific functions--e.g., replication, transcription, or recombination--each enriched in particular non-B DNA types. Human-specific ssDNA domains correlated with nervous system genes, whereas cancer and embryonic cells showed increased ssDNA in transposable elements. Our ssDNA analysis across ape T2T genomes uncovered conserved and species-specific DNA structural dynamics central to genome regulation.

genomics↗

bioRxiv2025

Environmental Novelty Modulates Rapid Cortical Plasticity During Navigation

In novel environments, animals quickly learn to navigate, and position-correlated spatial representations rapidly emerge in both the retrosplenial cortex (RSC) and primary visual cortex (V1). However, the role of plasticity in building these spatial representations, and how experience modulates this process, are not well understood. Here, we investigated the plasticity of spatial representations with real-time, cellular-resolution read and write control of neural activity using two-photon calcium imaging combined with holographic optogenetic stimulation in mice navigating virtual reality environments. Targeted stimulation of individual layer 2/3 neurons rapidly biased neural activity towards stimulation-paired locations in novel, but not familiar, environments. In contrast, RSC layer 5 neurons exhibited stimulation-induced plasticity regardless of environmental familiarity. These findings reveal a layer-specific, experience-dependent modulation of plasticity and offer a framework for how neocortical spatial representations strike a balance between stability of familiar environments with flexibility for continuous updates of relevant context information. HighlightsO_LIAll optical read-write approach reveals experience-dependent plasticity in cortex C_LIO_LIStimulating layer 2/3 neurons biases activity in novel but not familiar environments C_LIO_LILayer 5 neurons exhibit plasticity regardless of environmental familiarity C_LI

neuroscience↗

bioRxiv2025

Large-scale cellular-resolution read/write of activity enables discovery of cell types defined by complex circuit properties

The complexity of the mammalian brains vast population of interconnected neurons poses a formidable challenge to elucidate its underlying mechanisms of coordination and computation. A key step forward will be technologies that can perform large-scale, cellular-resolution monitoring and interrogation of distributed brain circuit activity in behaving animals. Here, we present an all-optical strategy for precise optogenetic activity control of [~]103 neurons and simultaneous activity monitoring of [~]104 neurons within and across areas of mouse cortex--an order-of-magnitude leap beyond previous capabilities. Tracking population responses following delivery of precisely-defined widely-distributed activity patterns to the visual cortex of awake mice, we were surprised to identify neurons robustly responsive to stimulation of diverse ensembles, defying conventional like-to-like wiring rules. These cells were primarily deep L2/3 somatostatin-positive (SST) interneurons with functional properties distinct from other SST neurons, and appeared to play a role in brain dynamics that could only have been identified through broad cellular-resolution circuit interrogation. Our work reveals the value of measuring large-scale circuit-dynamical properties of functionally-resolved single cells, beyond genetic and anatomical classification, to define and explore the roles of cell types in brain function.

neuroscience↗

bioRxiv2025

Exploring the correspondence between gene expressionand thalamic nuclei using the THALMANAC resource

The thalamus connects the sensory organs and major subcortical brain regions with the neocortex. The thalamus has long been divided into multiple discrete nuclei, based on cytoarchitecture, histochemical stains, and mesoscale connectivity. However, thalamic nuclei do not completely describe thalamic organization. For example, some boundaries between thalamic nuclei are disputed, whereas other nuclei are known to contain subdomains with distinct connectivity and function. Moreover, the correspondence between cellular gene expression and other properties of thalamic projection neurons remains to be established. Spatial analysis of single cell gene expression provides a basis for reevaluating thalamic organization. We present the THALMANAC, (THALamusMERFISH ANalysis and ACcess) a Findable, Accessible, Interoperable, Reusable and Reproducible (FAIRR) resource for exploring and analyzing single-cell transcriptomic variation in the thalamus. The THALMANAC provides streamlined access to thalamic gene expression data registered to the common coordinate framework and tools for quantitative analysis and visualization of these data, all encapsulated in a reproducible, cloud computing platform. Using this resource, we find that gene expression generally supports the parcellation of thalamus into distinct nuclei. Some nuclei, such as the anteromedial nucleus, are additionally composed of discrete subdomains, while other nuclei share patterns of gene expression or are arrayed on a spatial gradient of gene expression. The THALMANAC establishes spatial transcriptomic data as a foundation for delineating thalamic organization. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/679413v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1d517fcorg.highwire.dtl.DTLVardef@119dccdorg.highwire.dtl.DTLVardef@ef2cd6org.highwire.dtl.DTLVardef@68adac_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Genetic inhibition of IL-12β suppresses systolic overload-induced cardiac inflammation and heart failure development

Inflammation promotes heart failure (HF) development, and inhibition of IL-12{beta} simultaneously attenuates interleukin-12 (IL-12) and interleukin-23 (IL-23), two important proinflammatory cytokines. In this study, we used IL-12{beta} knockout (KO) mice to test the hypothesis that genetic inhibition of IL-12{beta} would attenuate transverse aortic constriction (TAC)-induced cardiac inflammation, hypertrophy, and dysfunction, as well as the consequent lung remodeling. IL-12{beta} KO in male and female mice significantly attenuated TAC-induced cardiac dysfunction as evidenced by improved left ventricular (LV) ejection fraction and fractional shortening. IL-12{beta} KO also significantly ameliorated the TAC-induced increase of LV weight, left atrial weight, lung weight, right ventricular (RV) weight, and their ratios to body weight or tibial length in male and female mice. In addition, IL-12{beta} KO significantly attenuated TAC-induced LV leukocyte infiltration, cardiomyocyte hypertrophy, fibrosis, and the consequent lung inflammation and remodeling. Moreover, IL-12{beta} KO reduced TAC-induced alterations of LV gene profile associated with inflammation and fibrosis, as shown by bulk LV RNA sequencing. Furthermore, we found that IL-12{beta} KO significantly attenuated TAC-induced LV accumulation of multiple immune cell subsets, activation of CD4+ and CD8+ T cells, and the percentage of central memory CD4+ and CD8+ T cells in the cardiac drainage lymph nodes. Finally, IL-12{beta} KO mice showed significantly reduced IFN{gamma}+CD8+ and CXCR3+CD8+ T cells in the drainage lymph nodes as compared with WT after TAC. These findings collectively demonstrate that IL-12{beta} plays a critical role in systolic overload-induced LV inflammation, remodeling, and dysfunction, likely through cardiac immune cell infiltration.

physiology↗

bioRxiv2025

Ultrasound-activated drug release with extracellular vesicles

Precise, noninvasive targeting and controlled drug release to the nervous system could transform both basic research and clinical therapy. In this work, we developed a focused ultrasound-responsive delivery system based on extracellular vesicles (EVs), which are naturally occurring and biocompatible phospholipid nanocarriers. To enable the ultrasound responsiveness, a lipid-gas phase transition material Perfluoropentane (PFP) was co-encapsulated with therapeutic agents into EVs via low-temperature sonication. The resulting EVs had a size of 100-200 nm and demonstrated efficient, on-demand release upon ultrasound stimulation. In primary cultured neurons, EVs loaded with lidocaine successfully suppressed calcium activity and showed minimum cytotoxicity. Finally, we demonstrated in vivo application of this system for modulation pain sensitivity in rats. Our EVs-drugs platform demonstrated a safe, and ultrasound-activated drug delivery with high spatiotemporal control, showing strong potential therapeutic applications.

bioengineering↗

bioRxiv2025

Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks

Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybins effect on connectivity is network-specific: strengthening the routing of inputs from perceptual and medial regions (homolog of default mode network) to subcortical targets, while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity, because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.

neuroscience↗

bioRxiv2025

PyMouse Lifter: Real Time 3-D Pose Estimation for Mice with Only 2-D Annotation Via Data Synthesis

Neural-network-based pose estimation models have become increasingly popular for quantitative analysis of mouse behavior, yet most recordings still use a single 2-D camera view and therefore lack the depth cues needed for accurate 3-D kinematics. Existing open-source 3-D mouse datasets for training deep-learning models cover only a narrow range of environments and do not generalize well to various laboratory settings. To overcome these limitations, we introduce PyMouse Lifter, a pipeline that automatically reconstructs 3-D mouse poses from ordinary 2-D top-view videos with minimal manual 2-D annotation. PyMouse Lifter combines (i) an anatomically realistic 3-D mouse model for automated data synthesis, (ii) a monocular depth estimation model, and (iii) a 2-D key-point estimation model, enabling accurate 3-D reconstruction (model-based 3D inference) in virtually any open-field arena without using depth or multiple camera views for reconstruction. We validate the system on multiple datasets against depth-camera ground truth and show that the lifted 3D trajectories yield improved behavior classification over 2-D data and can be implemented in real time.

neuroscience↗

bioRxiv2025

Receptor Tyrosine Kinase Profiling Identifies Chronic Constitutive Floodgate Oxidative Signaling in Glutathione-Independent Human Mammary Luminal Progenitor Cells

The human mammary epithelium contains a subset of luminal progenitor (LP) cells that are distinct from basal cells in both lineage potential and redox biology. LPs are uniquely equipped to tolerate oxidative stress through glutathione-independent mechanisms and have been implicated as candidate cells of origin in basal-like breast cancers. In this study, we identify the receptor tyrosine kinase (RTK) cKIT (CD117), as a defining feature of LPs and a key mediator of their expansion. cKIT is developmentally restricted to the LP compartment via Polycomb-mediated epigenetic repression in basal and luminal-committed cells. It is expressed in scattered epithelial cells within both ductal and alveolar regions of resting human mammary glands. Using RTK-engineered MCF10A models, we demonstrate that cKIT ligand/stem cell factor (SCF)-activated wildtype cKIT signaling is sufficient to drive proliferation in the absence of epidermal growth factor (EGF) and that cKIT is responsive not only to canonical ligands but also to hydrogen peroxide (H2O2). In primary human LPs, cKIT is rapidly phosphorylated upon exposure to SCF and H2O2, with concomitant AKT activation. These responses are enhanced when cKIT and EGFR signaling are co-engaged, suggesting a cooperative mitogenic program. In mammary gland, phosphorylation of the antioxidant enzyme PRDX1 is selectively detected in LPs, consistent with a floodgate model of redox signaling in which transient oxidative inactivation of peroxiredoxins (PRDXs) facilitates RTK signaling under elevated intracellular reactive oxygen species conditions. Clinically, elevated cKIT expression is associated with shorter progression-free survival in certain basal-like breast cancer, supporting a link between LP-like redox signaling states and aggressive tumor behavior. Together, these findings define a redox-integrated RTK signaling axis centered on cKIT that drives LP expansion and is associated with poor outcomes in a subset of basal breast cancers. This work establishes a mechanistic framework for targeting redox-responsive progenitor populations in both regenerative and oncologic context.

cancer biology↗