Biology subjects

Chen, Q.

Publications and source records attributed to Chen, Q..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

β-Glucan Modulates Monocyte Plasticity and Differentiation Capacity to Mitigate DSS-Induced Colitis

Trained immunity involves the reprogramming of innate immune cells after an initial exposure, resulting in heightened inflammatory responses to subsequent stimuli and enhanced bactericidal capacity during infection. However, this proinflammatory state could also exacerbate chronic conditions like inflammatory bowel disease (IBD), which is characterized by persistent inflammation and microbial imbalance. It remains unclear how trained immunity influences IBD pathogenesis and whether it can be harnessed therapeutically. In our study, pretreatment with {beta}-glucan reprogrammed bone marrow hematopoietic progenitors and peripheral monocytes, inducing a profound shift in monocyte plasticity and significantly reducing the severity of dextran sulfate sodium (DSS)-induced colitis. Adoptive transfer of bone marrow or peripheral monocytes from {beta}-glucan-trained mice into naive mice conferred robust protection against colitis, demonstrating that this protective effect is transferable. Trained mice also displayed improved clearance of intestinal bacterial infections. Single-cell RNA sequencing revealed an expansion of reparative Cx3cr1 macrophages derived from Ly6Chi monocytes, correlating with accelerated colonic epithelial regeneration. Collectively, these findings reveal how {beta}-glucan-induced trained immunity modulates monocyte differentiation to ameliorate experimental colitis, highlighting the potential of harnessing trained immunity as a therapeutic strategy to recalibrate innate immune responses and restore gut homeostasis in IBD, shedding light for future clinical applications. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/653036v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1b969c2org.highwire.dtl.DTLVardef@1ce603dorg.highwire.dtl.DTLVardef@10582forg.highwire.dtl.DTLVardef@10d7de6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

UniCell: Towards a Unified Solution for Cell Annotation, Nomenclature Harmonization, Atlas Construction in Single-Cell Transcriptomics

Standardizing cell type annotations across single-cell RNA-seq datasets remains a major challenge due to inconsistencies in nomenclature, variation in annotation granularity, and the presence of rare or previously unseen populations. We present UniCell, a hierarchical annotation framework that combines Cell Ontology structure with transcriptomic data for scalable, interpretable, and ontology-aware cell identity inference. UniCell leverages a multi-task architecture that jointly optimizes local and global classifiers, yielding coherent predictions across multiple levels of the ontology-defined hierarchy. When benchmarked across 20 human and mouse datasets, UniCell consistently outperformed state-of-the-art tools, including CellTypist, scANVI, OnClass, and SingleR, in annotation performance, and sensitivity to low-abundance populations. In disease settings, UniCell effectively identified previously unseen cell types through confidence-guided novelty detection. Applied to 45 human and 23 mouse tissue atlases, UniCell enabled cross-dataset and cross-species harmonization by embedding cells into a unified latent space aligned with Cell Ontology structure. Moreover, when used to supervise single-cell foundation models, UniCell substantially improved downstream annotation accuracy, rare cell detection, and hierarchical consistency. Together, these results establish UniCell as a generalizable framework that supports high-resolution annotation, nomenclature standardization, and atlas-level integration, providing a scalable and biologically grounded solution for single-cell transcriptomic analysis across diverse biological systems.

bioinformatics↗

bioRxiv2025

Selective RNA sequestration in biomolecular condensates directs cell fate transitions

Recent studies have emphasized the significance of biomolecular condensates in modulating gene expression through RNA processing and translational control. However, the functional roles of RNA condensates in cell fate specification remains poorly understood. Here, we profiled the coding and non-coding transcriptome within intact biomolecular condensates, specifically P-bodies, in diverse developmental contexts, spanning multiple vertebrate species. Our analyses revealed the conserved, cell type-specific sequestration of untranslated RNAs encoding key cell fate regulators. Notably, P-body contents did not directly reflect active gene expression profiles for a given cell type, but rather were enriched for translationally repressed transcripts characteristic of the preceding developmental stage. Mechanistically, microRNAs (miRNAs) direct the selective sequestration of RNAs into P-bodies in a context-dependent manner, and perturbing AGO2 or alternative polyadenylation profoundly reshapes P-body RNA content. Building on these mechanistic insights, we demonstrate that modulating P-body assembly or miRNA activity dramatically enhances both activation of a totipotency transcriptional program in naive pluripotent stem cells as well as the programming of primed human embryonic cells towards the germ cell lineage. Collectively, our findings establish a direct link between biomolecular condensates and cell fate decisions across vertebrate species and provide a novel framework for harnessing condensate biology to expand clinically relevant cell populations.

cell biology↗

bioRxiv2025

Single-cell alternative polyadenylation analysis reveals mechanistic insights of COVID-19-associated neurological and psychiatric effects

COVID-19 is associated with increased risks of neurological and psychiatric sequelae. Alternative polyadenylation (APA) is ubiquitous in human genes, resulting in mRNA diversity, and has been validated to play a pivotal regulatory role in the onset and progression of a variety of diseases, including viral infections. Here, we analyzed the APA usage across different cell types in frontal cortex cells from non-viral control group and COVID-19 patients, and identified functionally related APA events in COVID-19. According to our study, the poly(A) site (PAS) usage is different among cell types and following SARS-COV-2 infection. Moreover, we found the genes with significant PAS level changes affected pathways related to RNA splicing, and neuronal development and function, suggesting that survivors of COVID-19 will have a high risk of these diseases and that alternative splicing functions cause these changes. Additionally, APA usage and its correlation with gene expression levels varied across genes, some prefer short isoform that is more stable to produce more proteins, while others may be regulated by different mechanisms. A total of 267 risk genes targeted by microRNAs for common neurological and psychiatric disorders were found to undergo significant changes in APA following infection. In conclusion, our comprehensive analysis of APA in neural cells from COVID-19 patients at the single-cell level elucidated changes in APA levels in the brains of SARS-COV-2-infected patients and confirmed that these changes impair the function of the nervous system, providing important insights for COVID-19-associated sequelae. HighlightsO_LIWe analyzed the changes in single-cell APA level in the frontal cortex after SARS-COV-2 infection and found that PAS usage is different among cell types and changed after infection. C_LIO_LIWe find that APA changes are related to RNA splicing, and neuronal development and function, such as synaptic plasticity, nervous system development, learning or memory and cognition, and the brain function may be impaired due to global gene expression and APA changes. C_LIO_LIA total of 267 risk genes for common neurological and psychiatric disorders were found to undergo significant changes in APA following infection, implying that APA alterations in specific genes could be a potential therapeutic target and predictive biomarker for neurological and psychiatric disease. C_LIO_LIAPA in infection samples results in the removal/addition of miRNA target sites in the 3'-UTR of genes. A total of 2404 miRNAs were predicted which suggests that the miRNAs target site information can indicate the impact of APA events and has the potential to be used as a predictive biomarker. C_LI

bioinformatics↗

bioRxiv2025

Representational dynamics during extinction of fear memories in the human brain

Extinction learning - the suppression of a previously acquired fear response - is critical for adaptive behavior and core for understanding the etiology and treatment of anxiety disorders. Electrophysiological studies in rodents have revealed critical roles of theta (4-12Hz) oscillations in amygdala and hippocampus during both fear learning and extinction, and engram research has shown that extinction relies on the formation of novel, highly context-dependent memory traces that suppress the initial fear memories. Whether similar processes occur in humans and how they relate to previously described neural mechanisms of episodic memory formation and retrieval remains unknown. Intracranial EEG (iEEG) recordings in epilepsy patients provide direct access to the deep brain structures of the fear and extinction network, while representational similarity analysis (RSA) allows characterizing the memory traces of specific cues and contexts. Here we combined these methods to show that amygdala theta oscillations during extinction learning signal safety rather than threat and that extinction memory traces are characterized by stable and context-specific neural representations that are coordinated across the extinction network. We further demonstrate that context specificity during extinction learning predicts the reoccurrence of fear memory traces during a subsequent test period, while reoccurrence of extinction memory traces predicts safety responses. Our results reveal the neurophysiological mechanisms and representational characteristics of context-dependent extinction learning in the human brain. In addition, they show that the mutual competition of fear and extinction memory traces provides a mechanistic basis for clinically important phenomena such as fear renewal and extinction retrieval.

neuroscience↗

bioRxiv2025

Small non-coding RNAs encapsulating mammalian cells fuel innate immunity

Cell surface RNAs, notably glycoRNAs, have been reported, yet the exact surface RNA compositions in different cell types remain unclear. Here, we introduce a comprehensive suite of methodologies for imaging, profiling, quantifying, and exploring the biological functions of specific surface RNAs. Utilizing these techniques, we have identified diverse non-coding RNAs present on mammalian cell surfaces. We confirm the membrane anchorage and quantify the abundance of several representative RNAs on human primary cells. Notably, we discover a significant prevalence of Y RNAs on the surfaces of human monocytes and B cells. We find that these Y RNAs on human monocyte surfaces enrich extracellular histones, regulating interleukin-6 (IL-6) gene expression and subsequent protein secretion upon histone stimulation via NF-{kappa}B and AP-1 activation. Our study not only presents effective approaches for investigating surface RNAs, but also uncovers a previously unrecognized immune activation pathway mediated by surface Y RNAs on monocytes. In briefA comprehensive profiling of surface RNAs across diverse mammalian blood cell types unveil abundant Y RNAs on the surface of human monocytes. Subsequent investigations uncover functional roles of surface Y RNAs on monocytes as "immune sentinel" to enrich extracellular histones, revealing a previously unknown pathway of innate immune activation. HighlightsNovel methodologies for cell surface RNA mapping, validation and functional interrogation. Sequencing of surface RNAs across various mammalian blood cell types offers detailed maps of surface RNAs. Abundant Y RNAs localize on human monocyte surfaces and capture extracellular histones released by adjacent ruptured cells. Surface Y RNAs enrich extracellular histones to facilitate transcription and secretion of IL-6 through NF-{kappa}B and AP-1 activation.

molecular biology↗

bioRxiv2025

Quantifying Uncertainty in Phasor-Based Time-Domain Fluorescence Lifetime Imaging Microscopy

The phasor approach to time-domain fluorescence lifetime imaging microscopy (FLIM) offers a powerful, fit-free method for analyzing complex fluorescence decay signals. However, its quantitative accuracy is fundamentally limited by noise--particularly photon shot noise--which introduces variability and bias in lifetime estimation and fluorophore unmixing. In this study, we present a theoretical uncertainty model for phasor-based time-domain FLIM that analytically captures the propagation of shot noise and quantifies its impact on phasor coordinates and fluorophore weight estimation. We validate the model using Monte Carlo simulations and experimental data acquired from standard fluorescent dyes and biological tissue samples. Our model improves the overall reliability and efficiency of phasor-based time-domain FLIM, particularly in photon-limited imaging applications.

bioinformatics↗

bioRxiv2025

SLC44A1 deficiency impedes myelin development in the central nervous system

Axon-wrapping myelin sheath is essential for the proper functioning of the central nervous system (CNS). Defects in myelination occur in various neurodevelopmental disorders. Human deficiency of the solute carrier 44A1 (SLC44A1) causes a new type of childhood-onset neurodegeneration with leukoencephalopathy. Currently, there is no effective treatment for this devastating disease, and little is known about its pathological mechanisms. In this study we identified that SLC44A1 is enriched in oligodendrocytes and required for myelin development in the CNS of zebrafish and rodents, which is crucial for normal motor coordination and cognitive function. Defective oligodendroglial maturation and myelinogenesis can be visualized by in vivo time-lapse imaging in the spinal cord of zebrafish with Slc44a1b deficiency. Mechanistically, SLC44A1 deficiency disrupts the expression of genes involved in phosphatidylcholine production pathway, and subsequently inhibiting phospholipid biosynthesis and disturbing the lipid composition of myelin sheaths. More importantly, supplementation with citicoline, a natural choline metabolite, restores developmental myelination in SLC44A1-deficient animals. These findings demonstrate that SLC44A1 is essential for CNS myelination and citicoline supplementation represents a potential therapeutic strategy to address the developmental hypomyelination.

neuroscience↗

bioRxiv2025

The GSA Family in 2025: A Broadened Sharing Platform for Multi-Omics and Multimodal Data

The Genome Sequence Archive Family (GSA family) provides a suite of database resources for archiving, retrieving, and sharing multi-omics data for the global academic and industrial communities. It currently comprises four distinct database members: the Genome Sequence Archive (GSA, https://ngdc.cncb.ac.cn/gsa/), the Genome Sequence Archive for Human (GSA-Human, https://ngdc.cncb.ac.cn/gsa-human/), the open Archive for Miscellaneous Data (OMIX, https://ngdc.cncb.ac.cn/omix/), and the Open Biomedical Imaging Archive (OBIA, https://ngdc.cncb.ac.cn/obia). Compared to the 2021 version, the GSA family has significantly expanded by introducing a new database member, the OBIA, and through comprehensive upgrades to the existing ones. Notable enhancements to the existing members include broadening the range of accepted data types, enhancing the quality control systems, fine-tuning the data retrieval system, and refining the data-sharing management mechanisms.

genomics↗

bioRxiv2025

Learning interpretable representation for context-specific transcription regulatory networks using a foundation model

Gene expression is shaped by transcription regulatory networks (TRNs), where transcription regulators interact within regulatory elements in a context-specific manner. Despite significant efforts, understanding the intricate interactions of transcription regulators across different genomic regions and cell types remains a major challenge, largely due to data sparsity. Here, we introduce ChromBERT, a foundation model pre-trained on large-scale human ChIP-seq datasets. ChromBERT effectively captures the interaction syntax of approximately one thousand transcription regulators across diverse genomic contexts, generating interpretable representations of context-specific TRNs and their constituent regulators. Fine-tuned for various transcription regulation tasks, ChromBERT demonstrates superior performance in imputing previously unseen cistromes and modeling regulatory effects and dynamics in specific cell types. Notably, ChromBERT adapts its TRN representations for cell-type-specific tasks, providing deep insights into the roles of transcription regulators underlying observed regulatory effects or dynamics without requiring cell-type-specific genomic data for each regulator. By overcoming the limitations of sparse transcription regulator data, ChromBERT significantly enhances our ability to model, interpret, and predict transcriptional regulation across diverse biological contexts.

bioinformatics↗

bioRxiv2025

Cortactin regulates metastatic dormancy of circulating tumor cells by suppressing mTOR-dependent senescence

Metastatic dormancy often refers to the stable cell cycle arrest of disseminated tumor cells (DTCs) at distant sites. However, whether circulating tumor cells (CTCs) in the blood microenvironment can enter a dormant state prior to extravasation and becoming DTCs remains unclear. Using patient-derived melanoma CTC lines and animal explant models (CDX), we identified a previously unrecognized role of the cytoskeletal regulator cortactin (encoded by CTTN) in controlling mTOR/p53-dependent senescence and metastatic dormancy. Cortactin was localized to Rab7-postive endosomes and engaged in late endosomal tethering and homeostasis. The depletion of cortactin resulted in the accumulation of aberrantly enlarged late endosomal aggregates that were positive for Rab7 and mTOR. The mTOR protein complex was accumulated and activated within these abnormal vesicular structures, leading to robust p53 activation through phosphorylation at serine (S) 15 and S33 sites. Consequently, melanoma CTCs underwent G0/G1 cell cycle arrest and entered cellular senescence. This unusual oncogene-induced senescence (OIS) mechanism was characterized by SASP upregulation, {beta}-galactosidase activity, depletion of Ki-67 and Lamin B1, and elevated mitochondrial ROS (mtROS) levels. Notably, a positive feedback loop between p53 and mtROS was essential for maintaining stable senescence in CTCs. In preclinical CDX mouse models, we developed a sequential therapeutic strategy combining cortactin depletion with anti-Bcl-xL senolytic drugs. Such "One-two punch" treatment strategy effectively eliminated viable CTCs and suppressed metastatic tumor growth in vivo. Thus, targeting cortactin to induce CTC senescence, followed by senolytic therapy, may represent a promising strategy to block CTC-mediated metastatic progression.

cancer biology↗

bioRxiv2025

De novo design of miniprotein agonists and antagonists targeting G protein-coupled receptors

G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, but the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational de novo design methods and a high throughput "receptor diversion" microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity, and the use of these methods to generate agonists for MRGPRX1, NK1R and CCR5, as well as antagonists for CXCR4, CCR5, OXTR, GLP1R, GIPR, GCGR, PTH1R and CGRPR.. Cryo-electron microscopy data reveals atomic-level agreement between designed and experimentally determined structures for CGRPR- and CXCR4-bound antagonists and MRGPRX1-bound agonists. Our de novo design and screening approach opens new frontiers in GPCR drug discovery and development.

bioengineering↗

bioRxiv2025

The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming

Acute myocardial infarction (MI) is a leading cause of morbidity and mortality, and therapeutic options remain limited. Endogenously generated nitric oxide (NO) is highly cardioprotective, but protection is not replicated by nitroso-vasodilators (e.g., nitrates, nitroprusside) used in clinical practice, highlighting specificity in NO-based signaling and untapped therapeutic potential. Signaling by NO is mediated largely by S-nitrosylation, entailing specific enzymes that form and degrade S-nitrosothiols in proteins (SNO-proteins), termed nitrosylases and denitrosylases, respectively. SNO-CoA Reductase 2 (SCoR2; product of the Akr1a1 gene) is a recently discovered protein denitrosylase. Genetic variants in SCoR2 have been associated with cardiovascular disease, but its function is unknown. Here we show that mice lacking SCoR2/Akr1a1 exhibit robust protection in an animal model of MI. SCoR2 regulates ketolytic energy availability, antioxidant levels and polyol homeostasis via S-nitrosylation of key metabolic effectors. Human cardiomyopathy shows reduced SCoR2 expression and an S-nitrosylation signature of metabolic reprogramming, mirroring SCoR2-/- mice. Deletion of SCoR2 thus coordinately reprograms multiple metabolic pathways--ketone body utilization, glycolysis, pentose phosphate shunt and polyol metabolism--to limit infarct size, establishing SCoR2 as a novel regulator in the injured myocardium and a potential drug target. Impact statementMice lacking the denitrosylase enzyme SCoR2 demonstrate robust cardioprotection resulting from coordinate reprogramming of multiple metabolic pathways. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/642752v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@72bfbborg.highwire.dtl.DTLVardef@189cbc4org.highwire.dtl.DTLVardef@1a0cc51org.highwire.dtl.DTLVardef@1c61004_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Distinct Membrane Binding Properties of the Two Non-visual Arrestins

Membrane interactions play a crucial role in regulating arrestin activation and its binding to phosphorylated G protein-coupled receptors (GPCRs). Here, we utilize in vitro biophysical approaches and cell-based fluorescence intensity fluctuation analysis to systematically compare the membrane-binding properties of the two highly conserved arrestin subtypes, arrestin-2 and arrestin-3, under basal and stimulated conditions. Our findings reveal that arrestin-2 selectively engages the PI(4,5)P2-containing nanodiscs via its C-edge, whereas arrestin-3 primarily utilizes its finger loop to interact with negatively charged lipids. Notably, while the lipid bilayer alone does not activate arrestin, it synergistically enhances arrestin-2/3 activation in conjunction with a phosphorylated GPCR C-tail. Additionally, the spacing between receptor phosphorylation sites and the lipid bilayer modulates arrestin-membrane assembly. Live cell tracking further demonstrates that arrestin-2 and arrestin-3 exhibit distinct plasma membrane dissociation dynamics. These findings provide novel insights into the mechanisms governing arrestin activation and its functional interplay with membranes.

biochemistry↗

bioRxiv2025

Spatial transcriptomics elucidates the central role of cerebral vasculatures in the progression of Japanese encephalitis

The cellular and molecular mechanisms underlying the neuropathology of Japanese encephalitis virus (JEV) remain obscure. Herein, we designed Stereo-seq chips to simultaneously capture the in situ transcriptomes of both the host and JEV, constructing a comprehensive spatiotemporal pathological landscape for Japanese encephalitis (JE). This study reveals the central role of the vascular system in JE pathogenesis, particularly the meninges, which displayed the strongest signal of inflammation and cell death in the JEV-infected brain. The activation of the Ackr1+ endothelial cells, disruption of the blood-brain barrier, the migration of JEV-infected monocytes, secretion of immune factors by the infected cells, and the occurrence of pyroptosis and necroptosis form a positive feedback loop, resulting in an increasing influx of immune cells and tissue damage. JEV infection leads to neurological impairments, which may be attributed to the interaction between viral proteins and host cellular factors such as Stat1, Stat3, Nfkb1, and Sp1. As the vascular system serves as a central receiver and amplifier of inflammatory signals, regulating inflammation within the vascular system is essential in mitigating JE progression.

immunology↗

bioRxiv2025

Heterogeneous T cell response patterns within established clinical phases of Hepatitis B infection revealed through the rapid functional characterization of HBV-specific T cells in whole blood

Background & AimsThere is an unmet need for immunological biomarkers in chronic hepatitis B (CHB), where patient management relies on virological and biochemical markers despite the crucial role of virus-specific T cells in controlling viral replication and disease progression. To address this, we developed the HBV-cytokine release assay (HBV-CRA), a rapid, point-of-care test that measures multiple cytokines in whole blood after HBV-peptide stimulation. MethodsWe first assessed the assays sensitivity by spiking whole blood with engineered HBV-specific T cells. Next, we compared sensitivity and consistency of HBV-CRA to ex vivo IFN-{gamma} ELISpot assays. We then applied the assay in a cross-sectional study of 235 CHB patients and longitudinally in acute HBV patients during HBsAg sero-clearance. ResultsThe HBV-CRA detected T cell function in 80% of CHB cases and showed that elevated IL-2 and IFN-{gamma} levels after Core peptide stimulation were associated with HBsAg clearance. Importantly, unsupervised clustering identified distinct immune response patterns independent of established clinical and virological classifications. The assay also demonstrated the functional impact of NUC treatment on HBV-specific T cell responses. ConclusionsThe HBV-CRA is a rapid and easy-to-use assay that identifies immune profiles associated with HBsAg clearance and differentiates CHB patients based on antiviral T cell function. Its application in a large CHB cohort revealed that traditional disease phase classifications, based on viral and clinical parameters, cannot predict HBV-specific T cell profiles. The HBV-CRA has the potential to guide patient stratification for immunotherapeutic interventions.

immunology↗

bioRxiv2025

KYLO-0603, a novel liver-targeting, thyroid hormone recep-tor-β agonist for the treatment of MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. Kylo-0603 is a novel agonist for the thyroid hormone receptor {beta} (THR-{beta}) that has been developed by merging the structures of three acetylgalactosamine (GalNAc)-modified ASPGR ligands with a triiodothyronine (T3) analog. This unique design allows for both THR-{beta} activation and targeted delivery to hepatocytes, significantly reducing the risk of adversed effects related to increased systemic thyroid hormone-like effects. Additionally, it effectively lowers serum cholesterol by as much as 69.2% and low-density lipoprotein cholesterol (LDL-C) levels by up to 88.2% in the MASH mouse model. Meanwhile, Kylo-0603 was shown to reduce steatosis by up to 1.3 points (P < 0.001), inflammation by 1.8 points (P < 0.0001), and ballooning by 0.8 points (P < 0.01). The non-alcoholic steatohepatitis (NASH) activity score (NAS) decreased by up to 3.7 points (P < 0.0001), and the fibrosis score dropped by 0.6 points (P < 0.05). These findings suggest that Kylo-0603 is effective in enhancing liver tissue NASH status and inhibiting fibrosis progression. In summary, Kylo-0603, as a highly both tissue and target selective and low-toxicity THR-{beta} agonist, shows significant promise for treating MASH and is likely to emerge as a new therapeutic option for patients with this condition.

biochemistry↗

bioRxiv2025

Plat safeguards maternally aged oocytes against programmed cell death through activating the Erk1/2 pathway

The decline in oocytes quality and developmental potential with female reproductive aging is well recognized, yet the underlying mechanisms remain insufficiently investigated. In this study, through an integrative analysis of transcriptomes and morphologies of individual oocytes from young and aged mice, morphologically defective aged oocytes are identified with distinct transcriptomic features. Further analysis demonstrates that both apoptotic and ferroptotic pathways are activated in the defective aged oocytes, and simultaneously blocking both pathways reverses the defective morphology to the largest extent. The Plat gene, which encodes tissue-type plasminogen activator (tPA), is downregulated with oocyte aging, and Plat knockdown increases oocytes susceptibility to both apoptosis and ferroptosis. Mechanistically, tPA functions as an upstream signaling molecule for Erk1/2 activation by interacting with particular phosphorylation kinases such as Alk. Consequently, Plat loss downregulates Erk1/2 pathway activity in oocytes, leading to degeneration through programmed cell death. Supplementing exogenous tPA in in vitro oocyte maturation cultures reduces defect rate of aged oocytes, thereby improving oocyte quality and developmental potential. Collectively, Plat plays a pivotal role in protecting aged mouse oocytes from programmed cell death, and tPA supplementation may serve as a potential clinical strategy to enhance oocyte quality in females of advanced maternal age.

developmental biology↗