Biology subjects

Zhang, Z.

Publications and source records attributed to Zhang, Z..

At least 343 records · Page 19Linked to original sources

bioRxiv2025

LabOS: The AI Co-Scientist That Sees and Works With Humans

Modern science advances fastest when thought meets action. LabOS represents the first AI co-scientist that unites computational reasoning with physical experimentation through multimodal perception, self-evolving agents, and XR-enabled, embodied human-AI collaboration. To empower agentic AI with embodied intelligence, we built LabSuperVision, the first vision-language-model (VLM) benchmark spanning biomedical and materials science laboratories, designed to evaluate scientific perception and reasoning. This endowed LabOS with visual reasoning capabilities that surpass those of general-purpose models on laboratory-specific tasks. By connecting multi-model AI agents, smart glasses, and human-AI-robot collaboration, LabOS allows AI to see what scientists see, understand experimental context, and participate in real-time execution through immersive XR interaction and robotic autonomation. Across applications-from cancer immunotherapy target discovery to cell engineering-LabOS shows that AI can move beyond computational design to participation, turning the laboratory into an intelligent, collaborative environment where human and machine discovery evolve together.

bioengineering↗

bioRxiv2025

Elevated Temperatures Representing Heatwave Conditions Shift Active Nitrifying Communities and Their Viruses in Tidal Flats and Agricultural Soils

Global heatwave intensification associated with climate change will impact the nitrogen cycle, yet its effect on specific nitrifier groups or their interactions with viruses remains unclear. Using 13CO2-DNA-based stable isotope probing (SIP) coupled with metagenomics, we show that elevated temperatures associated with heatwave conditions restructure active nitrifying communities and their viruses in Yangtze River estuary tidal flats and adjacent agricultural soils. In tidal flats, high temperatures shifted active ammonia-oxidizing archaea and bacteria (AOA and AOB), and nitrite-oxidizing bacteria (NOB) from marine to terrestrial ecotypes. In contrast, heatwave conditions stimulated terrestrial ecotypes of AOA but suppressed AOB in agricultural soils. 13C-labeled nitrifier-infecting viruses also showed temperature-driven shifts in activity, lifestyle, and auxiliary metabolic genes in concert with hosts. Notably, AOA viruses carried the plastocyanin gene, potentially augmenting host metabolism. These findings demonstrate heatwaves drive complex shifts in nitrifier communities and their interactions with viruses, impacting global nutrient cycling under climate extremes.

microbiology↗

bioRxiv2025

POI-associated LMD-3 mutation impairs B12-regulated lysosomal function and reproductive capacity in C. elegans

Reproductive longevity decline is a key feature of aging and premature ovarian insufficiency (POI). While proteostasis collapse is implicated in reproductive aging, the molecular link remains elusive. Here, we engineered the clinically relevant W690C mutation into C. elegans lmd-3 gene, the human NCOA7 ortholog, to establish a valuable in vivo POI model. The mutation severely compromises LMD-3 protein stability and expression, leading to a profound collapse in reproductive capacity driven by germline apoptosis. We demonstrate that this defect drives catastrophic autophagic-lysosomal dysfunction, blocking degradation and causing proteotoxic accumulation of misfolded proteins. Crucially, we define this pathology as a functional B12 deficiency and show that mecobalamin (meCbl) supplementation successfully restores proteostasis. Together, these findings delineate a conserved genetic pathway from LMD-3 destabilization to reproductive failure and propose vitamin B12 as a readily translatable therapeutic intervention for age-related reproductive decline.

cell biology↗

bioRxiv2025

Functional and Structural Plasticity in Cocaine-Seeking Ensembles of the Nucleus Accumbens Core

Relapse vulnerability in substance use disorder (SUD) is primarily driven by cue-induced activation of neurons within the nucleus accumbens core (NAcore), among other contributing factors. Neuronal ensembles within the NAcore, defined here as selectively co-activated neurons during specific behavioral experiences, are essential during cocaine sensitization and recall. While transient synaptic plasticity (t-SP) has been widely observed in general neuronal populations within the NAcore during reinstatement, its ensemble-specific dynamics remain unclear. Here, we used c-Fos-TRAP2-based tagging to identify cocaine-seeking ensembles in mice following cocaine intravenous self-administration, extinction, and cue-induced reinstatement. Structural spine plasticity was assessed via confocal microscopy, and functional changes were measured using whole-cell electrophysiology across multiple reinstatement time points. Ensemble neurons exhibited enhanced dendritic spine head diameter (dh) and AMPA/NMDA (A/N) ratios following cue exposure, consistent with t-SP. Notably, spine classification revealed a reduction in mature spines during reinstatement, suggesting morphological remodeling rather than new spine formation in both ensemble and non-ensemble cells. Non-ensemble neurons exhibited classical functional transient synaptic plasticity, characterized by increased A/N ratios but no significant changes in dh. To begin assessing if presynaptic vesicle release impacts t-SP, paired-pulse ratio analysis indicated no differences in population or time point. Importantly, ensemble neurons displayed elevated A/N ratio following cocaine exposure, suggesting prior silent synapse maturation. These findings demonstrate that t-SP is not uniformly distributed across NAcore neurons but differs significantly between ensemble and non-ensemble neurons. By linking ensemble identity to both structural and functional plasticity, this study refines our understanding of cue-induced relapse mechanisms. Significance StatementRelapse in substance use disorder is strongly driven by cue-induced reactivation of neuronal ensembles in the nucleus accumbens core. While transient synaptic potentiation has been widely described in bulk neuronal populations within the nucleus accumbens core, its ensemble-specific expression has remained unclear. Here, we combined c-Fos-TRAP2 tagging, confocal imaging, and slice electrophysiology to show that transient synaptic potentiation is selectively expressed in behaviorally relevant ensembles. By linking ensemble identity with structural and functional plasticity during cue-induced cocaine seeking, these findings refine current models of relapse and identify ensemble-specific plasticity as a potential target for therapeutic intervention.

neuroscience↗

bioRxiv2025

Visuospatial attention exerts opposite modulatory effects on explicit and implicit audiovisual subjective synchrony via the frontoparietal network

Synchronization and integration constitute two essential subprocesses of audiovisual binding, commonly indexed by explicit subjective synchrony (ESS) and implicit subjective synchrony (ISS), respectively. Previous studies have shown that spontaneous fluctuations in visual attention are associated with ESS, and that ESS and ISS are negatively correlated, consistent with the temporal renormalization theory. However, it remains unknown whether controlled manipulations of visuospatial attention can causally modulate ESS and ISS in opposite directions via distinct neural mechanisms. To address this question, we conducted two complementary EEG experiments. In Experiment 1, ESS was assessed using a spatially cued beep-flash synchrony judgment task and the point of subjective simultaneity (PSS). In Experiment 2, ISS was measured using fusion and fission variants of the sound- induced flash illusion, with the peak illusion rate (PIR) as the behavioral index. This dual-paradigm design enabled direct comparison between explicit and implicit synchrony under matched attentional manipulations. Behaviorally, asymmetric allocation of visuospatial attention between auditory- and visual-leading conditions induced opposite shifts in PSS and PIR, specifically in the fusion variant. At the neural level, prestimulus frontal theta oscillations were associated with variations in PSS, whereas bilateral frontotemporal and left posterior beta oscillations were associated with variations in PIR. These results demonstrate that visuospatial attention exerts opposite modulatory effects on ESS and ISS through distinct oscillatory dynamics, providing causal evidence for the temporal renormalization theory and advancing understanding of how attentional control shapes multisensory temporal binding.

animal behavior and cognition↗

bioRxiv2025

Psoralen Enhances Direct Cardiac Reprogramming via PPARα Activation and Promotion of Mitochondrial Fission

BACKGROUNDCell-based therapy is a promising strategy for heart repair and regeneration. However, its clinical application has been hampered by the low efficiency of cell direct reprogramming and the immature state of the inducing cells. Developing novel strategies to enhance direct reprogramming efficiency and yield mature functional cardiomyocytes remains a critical challenge. METHODSWe evaluated the effect of Psr on cardiac reprogramming using RepSox and Forskolin (RF) as the baseline cocktail. Reprogramming efficiency, cardiomyocyte marker expression, and calcium handling were assessed by RT-qPCR, immunofluorescence. Ultrastructural features were examined by transmission electron microscopy. Metabolic profiles were analyzed using Seahorse assays. Transcriptomic changes were explored by RNA sequencing, followed by pathway and protein-protein interaction analyses. A myocardial infarction (MI) mouse model was used for in vivo validation. RESULTSSupplementation with Psr (10 M) markedly enhanced the induction of induced cardiomyocytes (iCMs), leading to earlier appearance of beating clusters (day 1 vs. day 6-8), improved sarcomere organization, robust calcium transients, and higher energy metabolism. Transcriptomic profiling identified activation of the PPAR signaling pathway, with PPAR, RXRG, and UCP1 as central regulators. Mechanistically, Psr promoted mitochondrial fission, thereby facilitating metabolic remodeling essential for cardiomyocyte maturation. In vivo, RF+Psr treatment significantly improved cardiac function and reduced fibrosis after MI compared to RF alone. CONCLUSIONPsr enhances direct cardiac reprogramming by activating PPAR signaling and promoting mitochondrial fission. These findings provide a novel mechanistic framework and suggest psoralen as a promising natural enhancer for cardiac regeneration strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/681288v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@13a5d27org.highwire.dtl.DTLVardef@b9cce5org.highwire.dtl.DTLVardef@3afef8org.highwire.dtl.DTLVardef@1398972_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

FlexRibbon: Joint Sequence and Structure Pretraining for Protein Modeling

AO_SCPLOWBSTRACTC_SCPLOWProtein foundation models have advanced rapidly, with most approaches falling into two dominant paradigms. Sequence-based language models (e.g., ESM-2) capture sequence semantics at scale, and a number of recent works incorporate structural signals into sequence encoders. MSA-based predictors (e.g., AlphaFold 2/3) achieve accurate folding by exploiting evolutionary couplings, but their reliance on homologous sequences makes them less reliable in highly mutated or alignment-sparse regimes. We present FlexRibbon{ddagger}, a pretrained protein model that jointly learns from amino acid sequences and three-dimensional structures. Our pretraining strategy combines masked language modeling with diffusion-based denoising, enabling bidirectional sequence-structure learning without requiring MSAs. Trained on both experimentally resolved structures and AlphaFold 2 predictions, FlexRibbon captures global folds as well as flexible conformations critical for biological function. Evaluated across diverse tasks spanning interface design, intermolecular interaction prediction, and protein function prediction, FlexRibbon establishes new state-of-the-art performance on 12 different tasks, with particularly strong gains in mutation-rich settings where MSA-based methods often struggle.

molecular biology↗

bioRxiv2025

Kingdom-wide evolutionary characterization of RNA editing factors in Archaeplastida

RNA editing, a post-transcriptional modification in plant mitochondria and plastids, is essential for environmental adaptation and diverse physiological processes. Despite extensive identification of RNA editing factors, primarily including pentatricopeptide repeat (PPR), multiple organelle RNA editing factor (MORF), organelle RNA recognition motif-containing (ORRM), and organelle zinc finger (OZ) proteins, their evolutionary history remains poorly understood. Here, we perform kingdom-wide evolutionary analyses across 364 high-quality Archaeplastida genomes and find massive PPR gene expansions in early-diverging land plants, predominantly driven by dispersed duplication associated with retroposition. Furthermore, integrative analyses indicate that DYW subgroup PPR genes have been horizontally transferred from plants to bdelloid rotifers, potentially enhancing the recipients adaptation to ultraviolet radiation. MORF proteins, accessory partners of PPRs, possess MORF hallmark domains structurally similar to protein-folding peptidase S8 propeptide/proteinase inhibitor I9 domains, suggesting a role in protein folding during RNA editing. Considering diverse domain compositions, we reclassify MORF, ORRM, and OZ proteins and uncover prevalent hallmark domain fusions. Together, these findings illuminate the kingdom-wide evolution of plant RNA editing machinery.

evolutionary biology↗

bioRxiv2025

Rapid inversion of singleton distractor representations underlies learned attentional suppression

In visually complex and dynamically changing environments, humans must often filter out salient but task-irrelevant stimuli. Prior work shows that with repeated exposure to color singleton distractors, individuals can learn to divert attention away from these salient items. However, the neural mechanisms supporting such attentional suppression remain unclear. The present study examined the temporal trajectories of singleton distractor representations during visual search to address this gap. Using multivariate pattern analyses of EEG data in human subjects (N = 40, 30 females, 10 males), we identified two clusters of decodable singleton distractor representations: an early cluster from 100-200 ms and a later cluster from 200-400 ms. Temporal generalization analyses showed that the later representations were inverted versions of the early ones. Importantly, stronger late, but not early representations, predicted faster search responses, suggesting that the later signals support distractor suppression. This representational inversion facilitates suppressing singleton distractors in the spatial priority map. Comparing decoding evidence across locations revealed that singleton distractor locations were suppressed relative to non-singleton distractors. Moreover, comparing the neural coding of locations revealed that the spatial organization in the singleton distractor neural space was inverted relative to that in the target neural space. Together, these findings reveal a rapid representational inversion underlying salient distractor suppression at the onset of visual search. This inversion of singleton distractor signals was likely driven by top-down control mechanisms that transform bottom-up saliency signals, producing an inverted arrangement of target and distractor information within a shared neural space. Significance StatementA primary goal of attention is to select relevant information while ignoring irrelevant input from the external environment. Although the mechanisms of attentional enhancement have been extensively studied, the mechanisms underlying attentional suppression remain less well understood. While prior work has made important progress in identifying when attentional suppression is engaged, the neural mechanisms that implement suppression are still unclear. Here, we show that neural representations of salient singleton distractors undergo a rapid inversion approximately 200 ms after search onset. These inverted representations can subsequently be read out as suppression signals during the computation of spatial priorities. Together, our findings suggest that transforming initial pop-out distractor signals into an inverted representational format might drive rapid attentional suppression and support goal-directed visual search.

neuroscience↗

bioRxiv2025

STRIDE: A Sequencing Depth-Insensitive Metric for Robust Comparison between Sparse Chromosome Conformation Capture Data

The study of three-dimensional (3D) genome organization has been revolutionized by high-throughput chromatin conformation capture technologies (Hi-C) or its derivatives. However, the dependency on sequencing depth severely restricts the reliability and accuracy of existing Hi-C tools, especially in single-cells. To address this issue, we introduce a novel computational framework based on the mean first passage time (MFPT) in Markov chain theory, which transforms chromatin contact matrices into a robust, distance-based representation. We demonstrate that MFPT representation is inherently insensitive to sequencing depth. Leveraging this transformation, we develop STRIDE (Spatial Topological Representation of Interaction Distance Evaluation), a parameter-free metric for library similarity. STRIDE is resilience to sparse and noisy data, insensitive to technical variabilities, and facilitates unsupervised embedding from single-cell Hi-C, enabling accurate delineation of cellular states and developmental trajectories. In conclusion, as a reliable computational framework for sparse and noisy data, STRIDE may serve as a base for wide range single-cell 3D genome analysis that used to be inconceivable.

bioinformatics↗

bioRxiv2025

Functional interrogation uncovers a critical role for a high-plasticity cell state in lung adenocarcinoma

Plasticity--the ability of cells to undergo phenotypic transitions--drives cancer progression and therapy resistance1-3. To date, strategies targeting cancer plasticity have not advanced to the clinic due to a lack of fundamental understanding of the underlying mechanisms. Recent studies have suggested that plasticity in solid tumors is concentrated in a minority subset of cancer cells4-6, yet functional studies interrogating this high plasticity cell state (HPCS) in situ are lacking. Here, we developed mouse models enabling detection, longitudinal lineage tracing, and ablation of the HPCS in autochthonous lung tumors in vivo. Using lineage tracing, we uncover the HPCS cells are dedifferentiated but possess high capacity for cell state transitions, giving rise to both early neoplastic (differentiated) and advanced lung cancer cell states in situ. Longitudinal lineage tracing using secreted luciferases reveals HPCS-derived cells harbor high capacity for growth when compared to bulk cancer cells or another defined cancer cell state with features of differentiated lung epithelium. Suicide gene-mediated ablation of the HPCS in early neoplasias abrogates tumor progression. Ablating HPCS cells in established tumors by suicide gene or HPCS-directed CAR T cells robustly reduces tumor burden, whereas ablation of a differentiated lung cancer cell state had no effect. We further demonstrate that the HPCS gives rise to therapy-resistant cell states, whereas ablation of the HPCS abrogates resistance to chemotherapy and oncoprotein-targeted therapy. Interestingly, an HPCS-like state is ubiquitous in regenerating epithelia and in carcinomas of multiple other tissues, revealing a convergence of plasticity programs. Our work establishes the HPCS as a critical hub enabling reciprocal transitions between cancer cell states, including acquisition of states adapted to cancer therapies. Targeting the HPCS in lung cancer and in other carcinomas may suppress cancer progression and eradicate treatment resistance.

cancer biology↗

bioRxiv2025

IGP receptors act as redox sensors to mediate broad-spectrum disease resistance induced by cellooligomers

Cys-oxidation is a well-established post-translational regulator of intracellular protein function, yet its role in extracellular receptor-mediated signaling remains poorly understood. Here, we investigate the LRR-Malectin receptor-like kinase IGP1, a key receptor for plant cell wall damage-associated molecular patterns (DAMPs). We demonstrate that IGP1 directly recognizes cellooligomers with a degree of polymerization [≥] 3 via a conserved binding groove in its LRR domain, not the malectin domain as anticipated. Strikingly, a pair of cysteines within the malectin domain functions as a redox sensor, undergoing hydrogen peroxide-induced oxidation that sterically reduces ligand binding affinity and attenuates immune signaling. Phylogenetic analyses reveal that IGP originated after the terrestrialization of plants, and is an evolutionarily conserved redox sensor in land plants. Functional studies in Arabidopsis (Arabidopsis thaliana), wheat (Triticum aestivum), and soybean (Glycine max) confirm that the IGP-cellooligomer module confers broad-spectrum disease resistance. Our work uncovers a unique mechanism where ligand perception and redox sensing are integrated into a single receptor to regulate DAMP-triggered immunity.

plant biology↗

bioRxiv2025

Hepatic ceramide synthesis links systemic inflammation to organelle dysfunction in cancer

Paraneoplastic syndromes arise when tumor-derived cytokines reprogram distant organs. Although mediators such as Interleukin-6 have been implicated, how these signals impair host organ function remains incompletely defined. Here, we identify a cytokine-lipid axis that drives hepatic autophagy dysfunction. Specifically, in Drosophila, the gut tumor-derived interleukin-like cytokine Upd3 induces the expression of the triglyceride lipase CG5SCC, which we named "cancer-associated lipid mobilizer (calm)", and the ceramide synthase schlank in the fat body. This upregulation rewires fat body lipid metabolism, resulting in an autophagic-flux blockade. Genetic reduction of either CG5SCC or schlank restores organelle homeostasis and mitigates paraneoplastic phenotypes. This mechanism is conserved in mammals: in mice, IL-6 upregulates the lipoprotein lipase Lpl and ceramide synthases which in turn trigger a hepatic autophagy-flux blockade; in humans, hepatic LPL and ceramide synthases expression correlates with poorer survival in hepatocellular carcinoma. Our findings position hepatic lipid metabolism rewiring, especially ceramide synthesis as a critical, conserved node coupling systemic inflammation to organelle dysfunction, and suggest this pathway as a possible therapeutic entry point for cancer-associated liver disorders.

genetics↗

bioRxiv2025

A knowledge-guided approach to recovering important rare signals from high-dimensional single-cell data

Single-cell transcriptomic data are high-dimensional, with many genes profiled in each cell. Dimensionality reduction is routinely applied to improve interpretability, remove noise and redundancy, and enable visualization. Most existing methods aim at preserving the most prominent data properties, which can lead to omission of rare but important signals. Here we propose a novel framework that uses knowledge-derived genes of interest to guide dimensionality reduction, which can help cluster rare cells and separate highly similar cell sub-populations. We demonstrate the utility of our framework in identifying endocrine cell subtypes in the pancreatic islet, highly similar hematopoietic sub-populations, and rare senescent cells.

bioinformatics↗

bioRxiv2025

LINE1 RNA dysregulation impairs chromatin accessibility in C9ORF72- and TDP-43-linked ALS/FTD

The long interspersed element-1 (LINE1) retrotransposon RNAs are abnormally elevated in various neurodegenerative disorders, but their pathogenic roles remain unclear. Here we investigated the mechanism of LINE1 RNA accumulation and its function in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with C9ORF72 repeat expansion and TDP-43 loss-of-function, the leading causes of familial and sporadic forms of these neurodegenerative diseases. We show that LINE1 RNA is dysregulated due to an impaired nuclear exosome targeting (NEXT) degradation pathway. Its elevation epigenetically increases chromatin accessibility, enhancing global transcription via a retrotransposon-independent mechanism. Reducing LINE1 RNA mitigates chromosomal abnormalities and improves the survival of disease-relevant neurons. These findings uncover an essential noncoding RNA function and regulatory mechanism of LINE1 in neurons, providing insights into disease pathogenesis and highlighting potential therapeutic targets for neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Aphid-derived cross-kingdom RNA dynamics underpin maize resistance

Aphids are major pests of maize (Zea mays), yet the molecular mechanisms underlying their interactions with host plants remain poorly understood. Here, we identified and functionally characterized long non-coding RNAs (lncRNAs) from the aphid-specific Ya gene family in the cereal-specialist aphids Rhopalosiphum maidis and R. padi. We showed that Ya genes formed lineage-specific clusters and were transcriptionally active across both species. Multiple Ya transcripts secreted into maize tissues exhibited remarkable stability compared with rapidly degraded aphid mRNAs and migrated systemically, as visualized in planta using an RNA switch-controlled RNA-triggered fluorescence system. RNA interference of Ya genes significantly reduced aphid fecundity, while ectopic expression of Ya lncRNAs in maize enhanced aphid colonization. Importantly, maize genotypes differing in aphid resistance selectively influenced the persistence of aphid mRNAs but not Ya lncRNAs, indicating a decoupled fate of distinct aphid RNA classes in planta. These findings establish Ya lncRNAs as cross-kingdom effectors critical for aphid virulence, and suggest new molecular markers for breeding aphid-resistant maize.

plant biology↗

bioRxiv2025

Understanding Fertility Intention Through the Lens of Family Functioning, Fertility Anxiety and Marriage-Fertility Views: A TPB-Based SEM Approach

ABSRTACTO_ST_ABSBackgroundC_ST_ABSGlobal fertility rates are declining, and despite Chinas three-child policy, the number of women of childbearing age continues to shrink. Fertility intention, a key predictor of fertility behavior, is shaped by factors such as socioeconomic stress, family functioning, and psychological traits. ObjectiveGrounded in the Theory of Planned Behavior, this study investigates how family functioning, marriage and fertility values, and fertility anxiety influence the fertility intentions of newlywed, childless young couples. MethodsA cross-sectional survey of 1,292 newlywed, childless couples in Yinchuan, Ningxia (2024) assessed demographics, family functioning (FAD), marriage and fertility values (MFV), and fertility anxiety (FA). Multiple logistic regression and structural equation modeling (SEM) were used. ResultsFamily functioning promoted intentions to have two or more children indirectly via positive communication and mediated by traditional MFV (44.4% of the total effect). Fertility anxiety showed no significant effect. Men preferred more children than women, and fertility intentions increased with age ConclusionsImproving family communication and reinforcing traditional values may help boost fertility intentions. Findings offer insight into the family-psychological mechanisms shaping fertility decisions.

animal behavior and cognition↗

bioRxiv2025

NPAS2 attenuates VSMC phenotypic switching in ascending thoracic aortic aneurysm via LPCAT3/PC-PUFA2S-mediated ferroptosis

Ascending thoracic aortic aneurysm (ATAA) is a life-threatening disorder with limited therapeutic options, critically linked to vascular smooth muscle cell (VSMC) phenotypic switching. Neuronal PAS Domain Protein 2 (NPAS2), a circadian rhythm-related transcription factor, regulates diverse physiological processes. However, the biological functions and underlying regulatory mechanisms of NPAS2 in VSMCs during ATAA pathogenesis remain to be elucidated. NPAS2 expression decreased in ATAA patients, PDGF-BB-treated HASMCs and BAPN-administrated mice. NPAS2 depletion facilitated VSMC phenotype switching. VSMC-specific NPAS2 knockout (NPAS2SMKO) mice exhibited aggravated ATAA. Mechanistically, NPAS2 depletion attenuates its transcriptional repression of LPCAT3, subsequently elevating the accumulation of phosphatidylcholines with two polyunsaturated fatty acyl chains (PC-PUFA2S), thereby promoting ferroptosis-induced VSMC phenotype switching and accelerating ATAA progression. Targeting NPAS2 represents a potential therapeutic strategy for ATAA treatment.

molecular biology↗