Biology subjects

Liu, Q.

Publications and source records attributed to Liu, Q..

At least 127 records · Page 7Linked to original sources

bioRxiv2026

Evaluating valid parameter regimes for biocircuits

Biocircuit functions are often valid only in specific parameter regimes, yet these regimes are rarely made explicit. We use a holistic analysis method based on regimes to derive validity conditions and introduce the Realizability Index (R-index), quantifying the size of the valid regions in log-parameter space. The framework is applied to Michaelis-Menten kinetics, Hill functions, and enzymatic negative-feedback adaptation, showing how circuit structure and experimental control variables shape functional realizability. Our analysis shows the Hill functions R-index goes to zero in sequential binding with increasing Hill coefficient. We also resolve an active debate about whether negative-feedback adaptation is realizable when competitive binding is taken into account, and demonstrates the superiority of the holistic R-index method over numerical parameter scans that lead to incorrect conclusions. R-index defines a validity-aware language for studying and designing functional biocircuits.

synthetic biology↗

bioRxiv2026

THIK-1 channel mediates microglial glucose sensing and modulates AgRP neurons

Microglia play essential roles in maintaining energy homeostasis, and their dysfunction contributes to metabolic disease. Although high-fat diet (HFD) exposure induces microglial activation, the underlying mechanisms remain poorly defined. Here, we identified a previously unrecognized role for THIK-1 channel in mediating glucose sensing of microglia in arcuate nucleus of the hypothalamus (ARH), during HFD-induced obesity. Pharmacological inhibition of THIK-1 channel with tetrapentylammonium (TPA) suppresses feeding and attenuates body-weight gain in diet induced obese mice. Mechanistically, inhibition of agouti-related peptide (AgRP) neurons is indispensable for TPA-induced hypophagia. Moreover, THIK-1 inhibition promotes microglial phagocytosis of perineuronal nets (PNNs), leading to reduced AgRP neuronal activity and feeding suppression. Together, these findings establish THIK-1 as a critical glucose sensor in hypothalamic microglia and uncover a microglia-dependent pathway through which overnutrition modulates AgRP neuronal activity via PNN remodeling to regulate energy balance, highlighting THIK-1 as a potential therapeutic target for treatment of diet-induced obesity.

neuroscience↗

bioRxiv2026

Isolation and Characterisation of Hair Follicle-Derived Melanocytes

Melanocytes are unique population of cells which produce melanin pigment. However, the property of melanocytes from hair follicle and epidermis, particularly, their molecular signatures remained largely unknown. In this study, we investigated the properties of epidermis and hair follicle melanocytes by biochemical and molecular biological assays. We found that epidermal melanocytes are differentiated and mature form of hair follicle melanocytes, and they are potentially related. Irradiation with NB-UVB did not induce cell death of hair follicle melanocytes as observed in epidermal melanocytes, but activate hair follicle melanocytes, promote proliferation and migration. In situ study suggested that after UVB irradiation, root sheath of hair follicles, particularly proximity of interfollicular epidermis and hair bulb become darker, suggesting migration and maturation of hair follicle melanocytes after UVB irradiation, rather than cell death. This observation provides hints and evidence to the relationship between hair follicle and epidermal melanocytes, helps to explain the contradiction of melanocytes cell death after UVB irradiation and the use of UVB in treatment of vitiligo lesion, as well as the perifollicular repigmentation phenomenon observed in vitiligo lesion after NB-UVB phototherapy.

cell biology↗

bioRxiv2026

Extracellular NAD(P) links hypersensitive response to localized acquired resistance

Effector-triggered immunity (ETI) generates cell non-autonomous signals that activate localized acquired resistance (LAR) in neighboring cells and systemic acquired resistance (SAR) in distant tissues. While SAR signaling has been extensively characterized, the molecular basis of LAR remains poorly understood. Here, we identify extracellular nicotinamide adenine dinucleotide (eNAD(P)) as a key damage-associated molecular pattern (DAMP) that mediates LAR. Using genetic, physiological, and cell death assays, we show that eNAD(P) and its receptor complex restrict hypersensitive response (HR)-associated cell death, promote cell survival, and are required for avirulent pathogen-induced LAR. In contrast, LAR is independent of the major SAR mobile signals N-hydroxypipecolic acid and azelaic acid, as well as certain other characterized DAMP pathways. Notably, ETI-mediated resistance remains largely intact in eNAD(P) pathway mutants, indicating that ETI directly restricts pathogens while simultaneously generating eNAD(P) signals to activate LAR. Our findings establish LAR as a mechanistically distinct immune layer and link HR-associated damage to eNAD(P)-dependent local immune reinforcement.

plant biology↗

bioRxiv2026

Poly(A)-tail-length-dependent surveillance of viral RNA by PABPC1 orchestrates broad-spectrum antiviral defense

RNA processing and modification are critical for virus replication and pathogenesis, yet how the host exploits viral RNA features--particularly the poly(A) tail--for antiviral defense remains unclear. Through multi-omics integration and systematic functional screening, we identify the poly(A)-binding protein PABPC1 as a broad-spectrum restriction factor against multiple coronaviruses. We demonstrate that PABPC1 preferentially binds viral RNAs bearing short poly(A) tails--distinct from the longer and more heterogeneous host poly(A) tails--and, in a poly(A)-length-dependent manner, recruits the mitochondrial exonuclease EXD2 to assemble a degradative RNA-protein complex. Both the recognition and subsequent degradation of viral RNA strictly depend on poly(A) tail length, enabling selective decay of short-tailed viral transcripts while sparing host mRNAs. Importantly, inflammatory signaling enhances the expression of PABPC1 and EXD2, suggesting its role as an inducible host defense pathway activated during viral infection. Capitalizing on this discovery, we engineered a synthetic fusion protein mimicking the PABPC1-EXD2 complex and achieved efficient delivery using lipid nanoparticles (LNPs). This rationally designed therapeutic exhibits robust suppression of coronavirus replication in both cellular and murine models. Collectively, our findings uncover a novel host antiviral strategy that targets a conserved viral RNA structural element and provide a conceptual framework for developing host-derived and broad-spectrum anti-coronavirus therapeutics.

microbiology↗

bioRxiv2026

Multiomics reveals epigenetic control of fibroblast activity after myocardial infarction and a key role for RUNX transcription factors

BackgroundAfter myocardial infarction (MI), cardiac fibroblasts proliferate and undergo a sequential differentiation process. They first transition into cardiac myofibroblasts, a transient and highly contractile state, and ultimately into matrifibrocytes, a more stable state that partially resembles chondrocytes. These dynamic transitions are essential for infarct healing and scar formation. While insufficient fibroblast activation can compromise infarct integrity, excessive activation promotes pathological fibrosis that impairs cardiac function. Despite its clinical importance, the transcriptional and epigenetic regulation of these transitions remain poorly understood. Elucidating underlying mechanisms is critical for developing strategies to fine-tune fibroblast activity during cardiac repair. MethodsWe performed bulk RNAseq, ATACseq, CUT&Tag, CUT&RUN, EMseq, and Hi-C on cardiac fibroblasts from uninjured and post-MI mouse hearts. In parallel, we conducted single-nucleus multiomic (snRNAseq and snATACseq) profiling across multiple time points after MI. Subsequent integrated analysis explored epigenetic mechanisms regulating cardiac fibroblast gene expression and activity. Using an improved computational strategy, we constructed gene regulatory networks to identify key transcription factors and biological processes regulated by these transcription factors. To assess the role of Runx1 specifically, we used tamoxifen-inducible, fibroblast-specific Runx1 knockout mice to evaluate transcriptional, epigenetic, and functional outcomes with the same genomic tools and additional complementary assays. ResultsCardiac fibroblasts undergo extensive chromatin remodeling after MI, which is highly correlated with changes in transcriptomic profiles. In contrast, the role of DNA methylation is relatively minor. Gene regulatory network analysis identified Runx1 as a central regulator of cardiac fibroblast proliferation and matrifibrocyte differentiation. In vitro and in vivo validation confirmed Runx1 as a key modulator of transcriptional and epigenetic changes in cardiac fibroblasts. Runx1 KO reduced cardiac fibroblast proliferation, disrupted the myofibroblast-to-matrifibrocyte transition, and affected macrophage cytokine expression through altered cardiac fibroblast-macrophage communication. Fibroblast-specific Runx1 knockout mice showed improved post-MI survival and reduced cardiac dilatation, especially in males. Simultaneous Runx2 deletion further enhanced the effects of Runx1 knockout. ConclusionsCardiac fibroblast activation and differentiation after MI are regulated by dynamic epigenetic changes. Runx1 plays a pivotal role in modulating cardiac fibroblast activities, and its deletion improves cardiac repair by mitigating maladaptive fibroblast responses. By illuminating the centrality of Runx1 in post-MI repair, this study identifies an actionable pathway for therapeutically steering fibroblast responses.

genomics↗

bioRxiv2026

PARP1 recruits SPRTN to DNA-protein crosslinks through a conserved poly-ADP-ribose binding domain.

DNA-protein crosslinks (DPCs) are toxic DNA lesions formed by the covalent attachment of proteins to DNA. Failure to resolve DPCs leads to genomic instability, premature aging, and cancer predisposition. Although multiple proteases and the 26S proteasome degrade DPCs, how these lesions are detected and marked for proteolysis remains unclear. Here, we show that poly-(ADP-ribose) polymerases (PARP1/2) sense DPCs and modify them with poly(ADP-ribose) (PAR) to promote repair via a SPRTN-Tdp1 axis. We discovered a Nudix homology domain (NHD) in SPRTN that mediates direct non-covalent PAR binding and is important for DPC repair. Loss of PARP1/2 activity or mutation of the SPRTN NHD leads to sustained DPCs. Single-molecule analysis revealed that SPRTN does not bind efficiently to the DPC, however after the addition of PARP1 in the presence of NAD+, SPRTN binding to the DPC was significantly increased. Our findings establish PARP1/2 enzymes as immediate DPC sensors, reveal PARylation as a signal marking DPCs for SPRTN-dependent degradation, and identify SPRTN as the first PARP-directed protease.

molecular biology↗

bioRxiv2026

Explainability methods from machine learning detect important drugs' atoms in drug-target interactions

Predicting drug-target interactions (DTI) with graph neural networks (GNNs) is hindered by their lack of interpretability. To address this, we benchmark four explainable artificial intelligence (XAI) attribution methods on GNN models trained for kinase and GPCR targets. We assess the methods consistency through atom-level intersection-over-union and validate their biological relevance by mapping attributed atoms to 3D protein-ligand structures. While consistency across methods was modest, consensus attributions were highly enriched for atoms directly contacting the binding pocket--up to 76% within 2 [A] in the kinase-inhibitor complexes. Notably, these attributed atoms were frequently found contacting experimentally important regulatory residues, such as those in the DFG motif. This indicates that XAI methods, despite their disagreements, can identify chemically meaningful ligand features, providing a foundation for developing more interpretable GNNs in drug discovery.

bioinformatics↗

bioRxiv2025

A gastric microbial chromatin remodeler drives gastric cancer progression and immune evasion by reprogramming the host epigenome

Emerging evidence highlights the crucial role of microbial communities in modulating cancer development and progression. In gastric cancer (GC), we identify Streptococcus anginosus (SA) as a tumor-resident oncobacterium that drives both tumor progression and immune evasion. We define a novel mechanism in which SA secretes extracellular vesicles (saEVs) that translocate the bacterial chromatin remodeler saSNF2 into host cell. There, saSNF2 partners with host transcription factor TEAD1--through its ATPase activity and participation in BAF complex assembly--to coordinately activate oncogenic transcription. This transkingdom interaction upregulates the palmitoyltransferase ZDHHC11, which in turn stabilizes PD-L1 via palmitoylation to establish an immunosuppressive niche, while also amplifying other TEAD1 target genes to fuel tumor progression. Functionally, saEVs promote tumor growth and limit CD8+ T-cell infiltration in vivo. Strikingly, pharmacological inhibition of ZDHHC11 reverses immune evasion and synergizes with anti-PD-1 checkpoint blockade. Our results establish SA as a multifaceted driver of GC and reveal the saSNF2-ZDHHC11 axis as a promising target to potentiate immunotherapy.

cancer biology↗

bioRxiv2025

Theta-Band Temporal Interference Stimulation of the Dorsal Anterior Cingulate Cortex Enhances Prediction Error Processing in Individuals With Food Addiction

BackgroundPrediction error (PE) signals encode discrepancies between expected and actual outcomes and are linked to medial frontal theta dynamics in the dorsal anterior cingulate cortex (dACC). However, causal evidence that dACC theta mechanisms contribute to PE gain in humans remains limited. Transcranial temporal interference stimulation (tTIS) enables non-invasive modulation of deep cortical targets and provides a strategy to probe dACC theta circuitry. ObjectiveTo determine whether theta-band tTIS targeting the dACC modulates the neural gain of prediction error encoding during reward processing. MethodsThirty-four participants with elevated food addiction-related symptoms were randomized in a single-blind, sham-controlled pre-post design to active theta-band tTIS or sham stimulation. Under satiety, participants completed a food incentive delay task while EEG was recorded before and after stimulation. Feedback-related negativity (FRN) was analyzed at mean and single-trial levels using mixed-effects models with behavioral and Rescorla-Wagner model-derived prediction errors. Stimulus-preceding negativity (SPN) indexed anticipatory processing. ResultsTheta-band tTIS selectively modulated feedback-stage prediction error encoding. It altered the trial-level FRN-prediction error slope, with pre-to-post changes differing between groups for both behavioral ({beta} = 1.74, p = .049) and model-derived prediction errors ({beta} = 1.77, p = .048). At the mean ERP level, FRN became more negative after active stimulation (t16 = 2.75, p = .014), whereas SPN was unaffected. ConclusionTheta-band tTIS targeting the dACC modulates neural sensitivity to prediction errors during reward feedback, providing causal evidence that medial frontal theta dynamics regulate the neural gain of prediction error encoding.

neuroscience↗

bioRxiv2025

NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer's disease

Synapse degeneration is a hallmark of neurodegenerative diseases1-3, including Parkinsons and Alzheimers disease (AD). Synapse loss has been known for decades as the strongest correlate with cognition and disease progression in AD patients4-8, but the molecular mechanisms that drive synapse degeneration remain elusive. Here, we identify Sarm1, a new class of NAD+ hydrolase required for Wallerian degeneration of periphery nerves after injuries9-12, as the key mediator of synaptic degeneration in AD brains. Sarm1 knockout largely reversed synapse loss, amyloid-{beta} (A{beta}) burden, and cognitive decline in 5XFAD mice. We found that Sarm1 is enriched in synaptic terminals and becomes activated in synaptic dystrophies adjacent to A{beta} plaques, leading to synapse degeneration and subsequent neuroinflammation. Sarm1 deletion in the AD mice prevented synaptic dystrophies and rescued short-term and long-term synaptic plasticity. Further, Sarm1 deletion protected synapses from C1q tagging and phagocytosis, and C1q-MERTK signaling in complement cascades 7,13-15 was significantly reduced. The reduced synapse degeneration, in turn, broke the feed-forward loop of "glia activation-neuroinflammation-A{beta} deposition". These data suggest that Sarm1 plays a key role in driving synapse degeneration in AD before C1q-tagging and phagocytic clearance, and targeting Sarm1 may offer a novel intervention to attenuate synapse degeneration and memory loss in AD. HighlightO_LISarm1 is enriched at presynaptic dystrophies and correlated with A{beta}. C_LIO_LIGenetic deletion of Sarm1 prevents synapse degeneration in AD. C_LIO_LISarm1 depletion is sufficient to reverse synaptic dysfunction and memory loss. C_LIO_LISarm1 depletion reduces A{beta} burden and neuroinflammation C_LIO_LIC1q--MERTK axis acts downstream of synaptic Sarm1 activation. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/695860v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@bd6b12org.highwire.dtl.DTLVardef@1c089e5org.highwire.dtl.DTLVardef@19d35fborg.highwire.dtl.DTLVardef@431364_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Closing the Sim-to-Real Gap: An End-to-End Robotic Ultrasound System Leveraging In Vivo Reinforcement Learning and 3D-Prior Guided Hybrid Control

Abdominal ultrasound is a crucial first-line diagnostic tool, yet its efficacy is inherently constrained by a strong dependency on operator skill, leading to significant inter-operator variability and limiting its widespread adoption. While robotic ultrasound systems with artificial intelligence have emerged to mitigate this, current approaches face critical limitations: they often rely on simulated or phantom data for training, which hampers generalizability, and employ control strategies that lack the flexibility to adapt to complex human anatomy. To address these challenges, this paper introduces a novel, end-to-end robotic system for autonomous abdominal scanning. Our methodology is systematic: it begins with coarse scan planning via RGB and 3D point cloud-based localization of key anatomical landmarks (e.g., xiphoid process). The core of our approach involves training a reinforcement learning scanning policy directly on live human volunteers, enabling the development of a strategy that is robust to anatomical diversity. This high-level policy is executed by a sophisticated hybrid force-position controller, enhanced with real-time normal vector calibration and 3D point cloud-based respiratory phase detection to dynamically adjust contact force, particularly during inspiration. This innovation proves critical for improving scan quality in subjects with higher Body Mass Index (BMI). Extensive validation against expert sonographers demonstrates that our system achieves high precision in standard plane recognition and superior scanning efficiency. Furthermore, to holistically assess performance where standard planes are difficult to acquire, we introduce a 3D reconstruction-based coverage metric. Results confirm that our system delivers strong adaptability and significantly improved consistency, marking a substantial step toward clinically viable, operator-independent ultrasound robotics.

bioengineering↗

bioRxiv2025

A K27-linked Ubiquitin Checkpoint Controls NOTCH Homeostasis

Cell surface receptors such as NOTCH1 must be tightly regulated to ensure developmental fidelity and prevent pathological activation. Although the proteolytic steps culminating in nuclear NOTCH1 signaling are established, how cells prevent excessive or uncontrolled activation has remained unresolved. Here we identify the autophagy-related protein UVRAG as a negative regulator of NOTCH1. Upon receptor activation, UVRAG, acting independently of autophagy, recruits and activates the E3-ligase ITCH to catalyze K27-linked ubiquitination of membrane-tethered NOTCH1, thereby licensing ESCRT-dependent lysosomal degradation. Disruption of the UVRAG-ITCH-ESCRT axis stabilizes activated NOTCH1 intermediates and amplifies oncogenic signaling. In T-cell leukemia models driven by constitutive NOTCH1 activity, restoring UVRAG expression reinstates receptor turnover, suppresses disease progression, and improves therapeutic response. These findings define a ubiquitin-directed safeguard circuit that enforces NOTCH1 signaling homeostasis and reveals a tunable axis for intervention in NOTCH1-driven cancers.

molecular biology↗

bioRxiv2025

Genetic Interaction of APOE-E-4 and PICALM rs3851179 is Associated With Dynamic Functional Connectivity in Healthy Middle-Aged Adults at Risk for Alzheimer's Disease

ObjectiveThis study investigates whether dynamic functional connectivity (dFC) dwell-time patterns derived from resting-state fMRI (rs-fMRI) can distinguish Alzheimers disease (AD) genetic risk profiles, specifically the APOE-{varepsilon}4 (A+) and PICALM rs3851179 (P+) variants, in cognitively healthy, middle-aged adults. ApproachWe estimated recurring dFC clusters from rs-fMRI data and quantified the dwell-time (total duration spent in specific connectivity states) for three cohorts: not-at-risk, A+P-, and A+P+. To evaluate the utility of these temporal features, group differences in dwell-time profiles were assessed, and logistic regression with permutation testing was employed to classify genotypes based on dFC patterns. Main resultsIndividuals in at-risk groups (A+P- and A+P+) exhibited significantly reduced dwell-time in left-hemisphere hubs compared to the not-at-risk group, aligning with known left-hemisphere vulnerability in early AD progression. The logistic regression models achieved above-chance discrimination of genotypes, with permutation tests confirming a significant trend when distinguishing not-at-risk individuals from the combined at-risk cohorts. SignificanceThese findings suggest that the temporal dFC features are sensitive to subtle functional brain alterations linked to AD genetic risk before clinical symptoms appear. Dwell-time features represent a promising physiological marker for early risk stratification and warrant further validation in larger longitudinal datasets. Our code is available at https://github.com/Shyamal-Dharia/APOE-PICALM-dFC-dwell-time.git.

neuroscience↗

bioRxiv2025

AlphaFold 3-powered discovery of phage proteins that inhibit bacterial transcription

Phages are the most abundant biological entities on Earth and play central roles in bacterial evolution and the emergence of new pathogens. Many phages encode proteins that specifically inhibit host RNA polymerase activity, thereby sabotaging and, in some cases, hijacking the host transcription machinery to serve their needs. Identification and characterization of these transcription inhibitors not only provide insights into the logic of transcription regulation but also inspire the design of antibiotics targeting bacterial transcription. Traditional methods for identifying new phage proteins that inhibit bacterial transcription are labor-intensive and require access to live phages. To overcome these limitations, we developed a highly efficient pipeline for AlphaFold 3-guided discovery of phage proteins that inhibit bacterial transcription. Using this pipeline, three phage proteins were identified and characterized. Structural and biochemical analyses demonstrated that these phage proteins bind to distinct sites on RNA polymerase and inhibit transcription via unprecedented mechanisms. This study showcases the power of AlphaFold 3 in discovering novel binders of large protein complexes, and the pipeline developed here could be readily adapted to screen modulators of other large targets, such as the ribosome, proteasome, and CRISPR-Cas systems.

molecular biology↗

bioRxiv2025

The CCC complex directs phagosomal maturation and bactericidal activity in macrophages through PI(3)P regulation

The evolutionarily conserved COMMD/CCDC22/CCDC93 (CCC) complex regulates endolysosomal function and is required for effective antibacterial immunity. However, the mechanisms linking the CCC complex to macrophage function remain poorly understood. Using bone marrow-derived macrophages, we found that CCC deficiency impaired bacterial clearance and disrupted phagosome maturation, as evidenced by defective phagosomal membrane remodeling, reduced phagosome-endoplasmic reticulum contacts, and impaired phagosome-lysosome fusion. These defects were independent of the CCC complex interaction partner, Retriever. CCC-deficient macrophages exhibited excessive phosphatidylinositol 3-phosphate (PI(3)P) accumulation on phagosomal membranes due to markedly reduced recruitment of the PI(3)P phosphatase MTMR2. Restoration of normal PI(3)P levels rescued bactericidal activity, establishing aberrant PI(3)P regulation as the principal defect affecting CCC-deficient macrophages. These findings identify a previously unrecognized Retriever-independent function of the CCC complex in regulating PI(3)P dynamics during phagosome maturation, a process essential for efficient bacterial clearance and innate immune defense.

cell biology↗

bioRxiv2025

Cryogenic 3D electron microscopy captures whole plant cell native ultrastructure

Volume electron microscopy (vEM) provides nanometer-scale, three-dimensional imaging of cells, but applying it to plant systems remains challenging. Cell walls, large vacuoles, and tissue thickness complicate sample preparation and cryogenic imaging. Here we report a cryogenic vEM (cryo-vEM) workflow for unstained plant protoplasts that achieves volumetric imaging of whole vitrified sorghum stem protoplasts without chemical fixation, dehydration, resin embedding, or heavy-metal staining. The method integrates optimized protoplast isolation, plunge-freezing vitrification for native-state preservation, automated cryogenic focus ion beam scanning electron microscopy (cryo-FIB-SEM) slice-and-view acquisition, contrast enhancement and stack alignment, and AI-assisted human-in-the-loop 3D segmentation. Using sorghum stem protoplasts as a demonstration, the workflow captured large-volume frozen-hydrated protoplast ultrastructure, allowing visualization of major organelles, including the nucleus, mitochondria, vacuoles, ER/Golgi-like membranes, lipid bodies, and subcellular features consistent with nuclear-envelope pores. We further quantified organelle volumes and surface areas from the segmented 3D data, highlighting the potential for quantitative cellular ultrastructure analysis. This cryo-vEM workflow provides a platform for near-native structural studies of isolated plant protoplasts.

plant biology↗

bioRxiv2025

Whole-Genome Population Genomics Reveals Lineage Structure and Adaptive Potential of Philaenus spumarius, the Principal Vector of Xylella fastidiosa in Europe

Philaenus spumarius (L.), the meadow spittlebug, is the principal European vector of Xylella fastidiosa. This xylem-feeding insect has a broad host range, ecological plasticity, and mobility, making it an efficient vector across diverse landscapes. Yet, major gaps remain in understanding its genetic diversity, migration patterns, and local adaptation, limiting effective control of X. fastidiosa outbreaks. To address these gaps, we worked with a global network of researchers and citizen scientists to assemble a geographically and ecologically diverse collection of P. spumarius samples. We generated a chromosome-level genome assembly for P. spumarius and high-quality assemblies for four related spittlebug species, providing a robust genomic framework for evolutionary and epidemiological studies. Resequencing 430 P. spumarius individuals from across the globe uncovered boreal, temperate, and semi-arid lineages shaped by geography and climate. The lineages vary in reproductive isolation and in the degree of mito-nuclear divergence. Iberian populations grouped with an individual identified as P. tesselatus contributing to regional genetic complexity. Genomic scans identified loci under selection in Apulian populations, including signatures in sulfotransferase (SULT) genes potentially linked to behavioural plasticity, host plant specialisation, or insecticide resistance in olive-growing regions. Migration analyses indicated limited long-distance dispersal but strong local connectivity, consistent with the rapid regional spread of X. fastidiosa. Together, these findings reveal the lineage structure and adaptive potential of P. spumarius, the key vector of X. fastidiosa in Europe. They underscore the importance of targeted surveillance of locally adapted populations and provide genomic tools for monitoring vector dynamics and mitigating emerging disease risks.

evolutionary biology↗