Biology subjects

Cui, Z.

Publications and source records attributed to Cui, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Structure and function of the DFCP1 membrane barrier responsible for ER microdomain organization in lysosome repair

The endoplasmic reticulum (ER) forms specialized microdomains that organize autophagy, lipid droplet formation, and the repair of damaged lysosomes. The PI3P-binding protein DFCP1/ZFYVE1 marks these microdomains, raising the question as to whether and how one protein could define such a subcompartment. Here we determine the structure of full-length human DFCP1 bound to membranes by cryo-electron tomography and single-particle cryo-electron microscopy. DFCP1 assembles into a helical coat, built from tetramers that stack around a constricted membrane tube. Its ATPase domains form the organizing core of the helix, while its ER-targeting domains insert deeply into the outer leaflet, and its FYVE domains grip PI3P. Coarse-grained molecular dynamics simulations show that the coat does not simply follow the curvature of the membrane but acts as a barrier to lipid diffusion, almost completely blocking the movement of its cognate lipid PI3P past the filament and concentrating it beneath the coat. Point mutations that break the assembly, membrane-insertion or PI3P-binding interfaces each impair lysosomal repair in cells, and the assembly is also required for the focal recruitment of the lipid transporter VPS13C. We propose that DFCP1 collars fence off a specialized ER microdomain, so that locally made lipids can reach sites of repair rather than escaping into bulk ER.

cell biology↗

bioRxiv2026

Pediatric brain charts reveal ADHD biotypes with distinct developmental, molecular, and therapeutic profiles

Attention-deficit/hyperactivity disorder (ADHD) exhibits profound clinical heterogeneity; however, its underlying neurobiological substrates remain unclear. Here, leveraging large - scale structural magnetic resonance imaging data from 12,663 typically developing children and 1,699 children with ADHD across Chinese and United States cohorts, we construct population specific pediatric brain charts via hierarchical Bayesian normative modeling to quantify individual deviations in cortical morphology. Data-driven clustering identifies two robust, cross - ethnically replicable ADHD biotypes: an infra - normal biotype characterized by widespread cortical thinning and a supra - normal biotype marked by cortical thickening. Multivariate analyses reveal distinct brain-behavior architectures: cortical deviations correlate preferentially with symptom severity in the infra-normal biotype but with both symptom severity and cognitive performance in the supranormal biotype. Clinically, the infra-normal biotype demonstrates a superior response to methylphenidate over atomoxetine, whereas the supra-normal biotype responds comparably to both. Transcriptomic analyses identify biotype-specific molecular signatures converging with ADHD genome-wide association study (GWAS) risk loci but exhibiting distinct expression patterns in the brain. These findings classify ADHD heterogeneity into neurobiologically distinct, clinically informed biotypes, providing a mechanistic framework for precision psychiatry in pediatric ADHD.

neuroscience↗

bioRxiv2026

CD24-dependent innate immune checkpoint targeting chimera disrupts TGF-β-driven immunosuppression to enhance anti-tumor therapy

The immunosuppressive tumor microenvironment (TME) poses formidable challenges for cancer immunotherapies. Among the complex TME landscape, the cytokine TGF-{beta}1 is an attractive soluble target for reinvigoration of anti-tumor immunity due to its pivotal function in immune cell suppression, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT) promotion, while immune checkpoint receptors exemplified by PD-1 and CD24 are promising surface targets. Though adaptive immune checkpoint inhibition is well established in clinical practice, TGF-{beta} blockade or innate immune checkpoint blockade is yet to be harnessed for tumor treatment. Here, leveraging CD24 overexpression on multiple tumor tissues and its unique recycling kinetics, we designed an innate Immune Checkpoint TArgeting Chimera (ICTAC) G01, a bifunctional CD24 antibody-TGF-{beta}1 receptor fusion protein that disrupts TGF-{beta}1 signaling by TGF-{beta}1 degradation instead of simple blockade and simultaneously inhibits the "don't eat me" CD24 signaling. We demonstrated that G01 effectively suppressed TGF-{beta}1-Smad signaling, reversed the EMT, and attenuated fibrotic collagen deposition. Additionally, it antagonized CD24 signaling to unleash robust antibody-dependent effector activity, further reprogramming the immunologically cold TME toward inflammatory phenotype. By selectively targeting malignant cells while sparing CD24-expressing B cells, G01 demonstrated a favorable safety profile. Notably, in patient-derived tumor fragments (PDTFs), G01 also inflamed the TME, underscoring its translational potential. Together, these results establish ICTAC as an effective strategy for tumor-specific receptor-mediated extracellular protein depletion, which supports its application for reversing TGF-{beta}1; and innate immune checkpoint-mediated tumor immunosuppression by concurrent targeting of both surface and soluble tumor-promoting factors.

immunology↗

bioRxiv2026

TLS-Sim: An Open-Source Toolkit for Individualized Transcranial Light Stimulation Modeling with Deep-Learning-Accelerated Simulation

Background: Accurate modeling of photon transport through the heterogeneous tissues of the human head is important for individualized transcranial light stimulation (tLS). However, high-precision Monte Carlo (MC) simulations can be computationally demanding, and existing general-purpose simulation tools do not provide an integrated, brain-oriented workflow. Methods: We developed TLS-Sim, a framework that integrates subject-specific head-model construction, multiple light-source configuration, GPU-accelerated MC photon simulation, visualization, and intracranial dosimetric analysis. Its central feature is a deep-learning-accelerated MC pathway, termed Flux-to-Flux, that estimates a high-photon-count energy-deposition field from a paired low-photon-count simulation. Sparse and full Monte Carlo fields were encoded using a three-dimensional variational autoencoder (VAE), and a three-dimensional velocity network was trained to transform the sparse latent representation toward the corresponding full-simulation representation. Results: We demonstrate the end-to-end toolkit and the Flux-to-Flux (F2F) pathway on a representative individualized head model evaluated across three source configurations. Relative to the sparse simulation, the learned prediction improved agreement with the full Monte Carlo reference by approximately +4 dB in signal-to-noise ratio on average, with correspondingly higher structural similarity and lower mean absolute error. Conclusions: TLS-Sim provides a modular, openly released computational framework for individualized tLS simulation and analysis. The Flux-to-Flux pathway is presented as an implemented capability that reduces the computational burden of high-photon-count simulation while improving spatial agreement with the full MC reference, most strongly at the low-fluence field boundaries where the sparse simulation is noisiest.

bioengineering↗

bioRxiv2026

Lanthanide protein biosensors with a single ion-binding site

Rising demand for rare earth elements, including lanthanides (Lns), has intensified environmental pressures and supply-chain vulnerabilities, motivating the development of bio-based methods for their extraction and separation. However, the lack of high-throughput assays for analysing the selectivity of lanthanide-binding proteins remains a key bottleneck in engineering bio-based Ln-extraction systems. Here, we report the development of high-throughput assays based on Ln-responsive protein biosensors. These {beta}-lactamase-based biosensors contain receptors with a single Ln-binding site derived from either lanmodulin or the AI-designed protein RF2. We established multiplexed colourimetric assays that quantify biosensor activity and selectivity in vitro and in the periplasm of E. coli. We further demonstrate that E. coli cells expressing these biosensors exhibit Ln-dependent survival in the presence of {beta}-lactam antibiotics. These platforms enable large-scale testing of Ln biosensors and Ln-binding proteins.

synthetic biology↗

bioRxiv2026

The evolutionarily conserved APP-Spastin cooperation regulates endolysosomal homeostasis and apoptotic cell degradation

Efferocytosis, the recognition, engulfment, and degradation of apoptotic cells by phagocytes, is essential for tissue homeostasis and development, and its failure contributes to chronic inflammation and neurodegeneration. The amyloid precursor protein (APP), a central pathogenic factor in Alzheimers disease, retains physiological functions independent of amyloid production that remain poorly understood. Here, we identify a conserved, non-amyloidogenic role for APP in regulating apoptotic cell degradation via the endolysosomal pathway. Using Drosophila APPL as a model, structure-function analysis demonstrated that the intracellular internalization domain of APPL, but not its secreted ectodomain, is required for efficient apoptotic cell degradation. Immunoprecipitation coupled with mass spectrometry revealed a physical interaction between APPL and the microtubule severing ATPase Spastin, mediated by the microtubule-interacting and trafficking domain of Spastin. APPL interacts with Spastin on endosomal microtubules and modulates the dynamics of the Spastin-ESCRT-III complex, enabling Spastin to sever microtubules and promote endosomal tubule fission. Loss of APPL disrupts this process, causing aberrant endosomal tubulation and impaired lysosome biogenesis. Furthermore, it compromises the function of residual lysosomes, characterized by reduced acidity, diminished proteolytic activity, and increased lysosomal damage, which ultimately impairs the degradation of engulfed apoptotic cells. Critically, this phenotype is evolutionarily conserved in C. elegans and mice. Together, these findings establish a conserved APP-Spastin axis that regulates endolysosomal homeostasis and apoptotic cargo digestion. This reveals a critical non-amyloidogenic function of APP in maintaining tissue homeostasis through efficient efferocytosis, with broad implications for inflammatory and neurodegenerative disorders that warrant further investigation.

cell biology↗

bioRxiv2026

A Tripartite Map of the Ventromedial Prefrontal Cortex

The ventromedial prefrontal cortex (VMPFC) has been repeatedly implicated in affect, valuation, and social cognition, yet how these diverse functions are organized within a single cortical territory has remained unresolved. Here, we integrate large-scale meta-analysis, individual-level task fMRI, artificial neural-network encoding models, and multimodal connectivity analyses to reveal the internal functional architecture of the human VMPFC. Across four complementary studies, we identify a robust tripartite organization along the anterior-posterior axis, comprising posterior affective, middle valuation, and anterior social functional motifs. Connectivity fingerprinting demonstrates that each motif is preferentially embedded within distinct large-scale brain networks, providing a mechanistic account of VMPFC functional specialization. This organization is reproducible at the level of individual subjects, generalizes to naturalistic stimuli, extends across development, and shows cross-species correspondence with non-human primates and multiple neurobiological markers. Together, these findings resolve a long-standing organizational question and establish a biologically grounded framework for interpreting VMPFC function.

neuroscience↗

bioRxiv2026

Structural basis for the ATP-dependence of omegasome biogenesis by DFCP1

Autophagosome formation begins at phosphatidylinositol 3-phosphate-enriched endoplasmic reticulum (ER) subdomains termed omegasomes. DFCP1/ZFYVE1 is recruited to omegasomes through its FYVE domains and has recently been shown to function as an ATPase involved in omegasome constriction and autophagosome biogenesis. However, the structural basis of DFCP1 ATPase activity and how nucleotide-dependent conformational states regulate omegasome dynamics remain unknown. Here, we determined the crystal structures of the DFCP1 ATPase domain in complex with either ADP or the non-hydrolyzable ATP analogue, AppNHp at near atomic resolution. We employed structure-guided mutagenesis to define residues required for DFCP1 function in cells. The structures reveal that the active site contains a trans-acting Arg271 finger coordinating the {psi}-phosphate and trans-acting His323 that stacks on the ATP adenine ring. ATP hydrolysis results in a conformational switch in the vicinity of Arg271, while contacts with His323 persist in the presence of ADP. Biochemical analyses of DFCP1 and its mutants show that DFCP1 forms ATP-dependent microdomains on membranes. Disruption of His323 and Arg271 uncouples nucleotide binding from ATP hydrolysis and alters the oligomeric state of the protein. Live-cell imaging of DFCP1 knockout cells reconstituted with wild-type or mutant DFCP1 further demonstrates that these biochemical defects translate into distinct omegasome phenotypes. Together, our data provides a structural-function framework for DFCP1 ATPase activity and reveals how distinct catalytic elements control omegasome dynamics in vivo. We propose that nucleotide-dependent assembly and hydrolysis-driven conformational changes enable DFCP1 to regulate omegasome formation and its progression toward autophagosome closure. Significance StatementDFCP1 organizes the ER subdomains known as omegasomes, which are sites of autophagosome biogenesis. DFCP1 is an ATPase whose catalytic activity is required for function, but the precise role of its ATPase activity is unknown. Crystal structures of the DFCP1 ATPase domain in the presence of a non-hydrolyzable ATP analogue and ADP reveal an Arg finger that operates in trans, such that dimerization is required for ATP hydrolysis, and ATP hydrolysis destabilizes dimers. Dimerization is also promoted by an adenine base-stacking interaction in trans with H323. These residues are important for DFCP1 clustering on membranes and omegasome constriction, clarifying that the role of ATP is to promote the dimerization of the ATPase domain and thereby control the organization of DFCP1 on membranes.

biochemistry↗

bioRxiv2026

Eleven deep-sea coral genome assemblies unveil insights into evolution, adaptation, and coral biodiversity

Deep-sea corals are vital in maintaining coral ecosystem biodiversity, yet their genetic characteristics remain largely unexplored. Here, we present 11 deep-sea coral genome assemblies, including four Hexacorallia and seven Octocorallia species, significantly contributing new genomic information across two orders. Our analysis reveals the historical dynamics of coral speciation and the influence of environmental factors on the evolution of coral reef ecosystems.Total of 126 horizontal gene transfer (HGT) events were detected, among which genes from the ancestor of symbiodiniaceae indicate that the ancestors of deep-sea corals may have inhabited shallow-sea environments. Notably, several of these HGTs are involved in phosphorus (PhnX/PhnW) and cholesterol (DHCR7) metabolisms within corals, indicating that HGTs may serve as an adaptive survival strategy for the coral holobionts. Deep-sea corals also rely on symbiotic bacteria to synthesize 10 essential amino acids (such as valine and tyrosine), retaining only partial amino acid synthesis capacity. In addition, we investigated the evolution of key biological rhythm genes and temperature adaptation in corals. The loss of key rhythm genes (e.g., clock and cry) in deep-sea corals and copy number difference of genes related to heat stress (e.g., Cbl-b and Rchy) revealed genetic difference between deep-sea and shallow-sea corals. Our new genome assemblies enhance the understanding of deep-sea coral evolution, biodiversity, and adaptation, providing a genetic foundation for coral conservation.

genomics↗

bioRxiv2026

ExMODE: A Multi-Omics Repository for Extremophile Adaptation and Bioprospecting

Extreme environments, though hostile to most life forms, host specialized extremophile communities that have redefined biological cognition and emerged as vital biotechnological resources, with their unique adaptive traits and bioactive molecules driving advances in multiple scientific and industrial fields. However, research on extremophiles is hindered by limitations in culture-based methods, fragmented multi-omics data with non-uniform annotation standards across repositories, the lack of cross-extreme comparative research in existing resources, and the singularity of data dimensionality that neglects key structural information, all of which restrict the functional interpretation of extremophile microbes and the exploitation of their bioprospecting potential. To tackle these challenges, we developed ExMODE (https://db.genomics.cn/exmode/), a comprehensive multi-omics database platform dedicated to extremophiles. It centrally integrates multi-omics data from diverse extreme habitats with a standardized annotation framework, resolving data fragmentation and enabling systematic cross-environment comparative analyses to elucidate extremophile adaptive mechanisms. Moreover, ExMODE aggregates multi-dimensional datasets including genes, genomes, secondary metabolite sequences and protein structures, overcoming the constraints of single-dimensional data and significantly improving the efficiency of biotechnological resource discovery from extreme microorganisms.

microbiology↗

bioRxiv2026

A previously unappreciated class of metal-dependent bile salt hydrolases from the human gut microbiome

Bile salt hydrolases (BSHs) are gut microbial enzymes that catalyze the deconjugation of glycine-or taurine-conjugated bile acids (BAs), a key step in shaping the BA pool in the human gastrointestinal tract and modulating host-gut microbiome interactions.1-3 All known BSHs are members of the N-terminal nucleophile (Ntn) hydrolase superfamily and share a conserved architecture and mechanism involving a nucleophilic active site cysteine.4,5 This knowledge has guided predictions and study of BSH activity in the gut microbiome6,7 as well as the development of BSH inhibitors8. Here, we report the discovery and characterization of a previously unknown BSH from the human gut bacterium Bilophila wadsworthia that belongs to the metal-dependent amidohydrolase superfamily and exhibits robust and specific activity toward taurine-conjugated bile salts. We show this secreted enzyme, metalloBSH, utilizes a metallocofactor for BA deconjugation, a mechanism distinct from that of canonical Ntn-type BSHs. MetalloBSHs are conserved in B. wadsworthia and present in many other Desulfovibrionaceae found in vertebrate gut microbiomes. Analysis of multi-omic datasets indicates metalloBSHs are expressed in vivo and correlate with BA metabolism. Overall, our findings reshape our understanding of BSH activity in the gut microbiome and highlight the promise of activity guided discovery in revealing previously overlooked gut microbial enzymes.

biochemistry↗

bioRxiv2026

IL12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer

Adoptive cell therapies used to treat advanced prostate cancer are being developed to target several tumor-associated antigens, including prostate-specific membrane antigen (PSMA). Chimeric antigen receptor (CAR) T cell therapy using the single chain variable fragment (scFv) derived from the humanized murine mAb clone, J591, as the antigen-binding domain has shown promising anti-tumor activity. However, it has also been associated with macrophage activation syndrome and other unwanted toxicities, highlighting the need for more specific and human-derived antigen-binders with optimized construct designs for improved safety and efficacy. Here, we optimize a human scFv-based PSMA-targeted CAR (hPSMA-CAR) with highly selective PSMA targeting. We further introduce a membrane-bound IL-12 (mbIL12) molecule, which enhances potency with increased T cell expansion, IFNy production and anti-tumor cell activity in vitro. Using two clinically-relevant bone-metastatic prostate cancer models, we show that mbIL12-engineered hPSMA-CAR T cells drive potent in vivo anti-tumor responses. In summary, we have developed a promising therapeutic that has potential to promote safe and effective treatment of advanced PSMA+ prostate cancer.

bioengineering↗

bioRxiv2026

Discovering macroscale functional organization on the structure of brain-like recurrent neural networks

Linking structure and function is a central topic in both neurobiology and artificial intelligence. Human brain functions are organized across the macroscale cortex into parcellations, modules, and hierarchies that can be inferred from intrinsic structural architecture, providing an interpretable and clinically meaningful framework for linking structure to function. While artificial neural networks have been successfully aligned with human cognition at the representational level, it remains unclear whether the structural principles linking brain anatomy and function can extend to artificial neural networks, and whether imposing brain-like structural constraints can induce comparable functional organization to that observed in the human brain. Here, we introduce BrainRNN, a brain-like recurrent neural network architecture inspired by macroscale human cortical structure. We show that under structural constraints, BrainRNNs selectively regulate the distribution of connectivity and recruit more activated units in association regions for higher-order cognitive capacity. Moreover, we demonstrate structure-function coupling in BrainRNNs and show that structural constraints enable macroscale functional organization, including functional modules and gradients, to emerge along topographic and topological axes, closely mirroring empirical findings in the human cortex. Together, these results demonstrate how multiple brain-like structural constraints jointly shape functional organization and enable function to be inferred from structure, highlighting the potential of structurally grounded artificial intelligence for neuroscientific research.

neuroscience↗

bioRxiv2026

Myeloid CD209 impairs T-cell activation by inducing ICAM-2-ERM-dependent cortical stiffening

Resistance to PD-1-based immunotherapy remains a major challenge in cancer treatment, especially in immunologically "cold" tumors characterized by T-cell exclusion and impaired effector function. Tumor-associated myeloid cells are important mediators of this resistance, but whether they directly suppress T-cell immunity through mechanical regulation remains unclear. Here, we identify DC-SIGN (CD209), a myeloid-expressed C-type lectin receptor, as a mechanosuppressive regulator of antitumor T-cell immunity. DC-SIGN is selectively enriched in tumor-infiltrating M2-like macrophages and monocytes, and its expression is associated with poor clinical response to PD-1 blockade and elevated TIDE scores across multiple cancer types. Mechanistically, DC-SIGN directly engages ICAM-2 on T cells and activates ROCK1-ERM signaling. This interaction increases T-cell cortical stiffness, destabilizes T cell-antigen-presenting cell interactions, and attenuates T-cell receptor signaling. Blocking the DC-SIGN-ICAM-2-ERM pathway restores T-cell activation and promotes CD8+ T-cell infiltration and effector function in mouse, humanized, and ex vivo human tumor systems. Importantly, DC-SIGN blockade overcomes resistance to PD-1-based immunotherapy in refractory and immunologically "cold" tumor models, and further enhances the response to PD-1 inhibition. Together, our findings define a myeloid-derived mechanical immune checkpoint and reveal T-cell mechanosuppression as a targetable mechanism of tumor immune evasion and immunotherapy resistance.

immunology↗

bioRxiv2025

Developmental deviations of structural connectivity in youths with ADHD predict symptom and treatment outcomes

Attention-deficit/hyperactivity disorder (ADHD) lacks validated biomarkers to track symptom development or guide treatment selection in youth. We quantified individual deviations from normative age-related trajectories of white-matter structural connectivity (SC) across two independent cohorts: 6,687 typically developing and 1,114 ADHD scans from the ABCD study, and 292 typically developing and 482 ADHD participants from a Chinese cohort. Youth with ADHD showed pronounced SC deviations, especially in higher-order association pathways. A subset of connections showed ADHD-specific developmental reductions in deviations beyond typical developmental patterns, and these changes mediated the age-related decline in ADHD symptoms. Longitudinal within-individual analyses demonstrated that decreases in deviation over two years tracked symptom improvement. Baseline deviations also predicted 12-week treatment response to atomoxetine, but not methylphenidate, and follow-up imaging revealed treatment-related reductions in deviation. Together, these findings identify SC deviation as a robust developmental biomarker with prognostic and theragnostic relevance for ADHD, supporting precision care through risk stratification, individualized pharmacotherapy selection, and objective monitoring of treatment effects.

neuroscience↗

bioRxiv2025

Emergence of Individualized Functional Topography in the Neonatal Brain

The early postnatal period represents a critical phase for establishing the brains fundamental architecture. However, how individualized functional topography emerges and shapes long-term cognition remains unknown. Using multimodal neuroimaging data from 419 neonates, we map personalized functional topographies in the first weeks of life and reveal their association with 18-month neurocognitive outcomes. Unique and stable functional topographies are already present at birth, with interindividual variability organized along a conserved sensorimotor-to-association hierarchy. These individualized maps encode early brain maturity and robustly predict cognitive, language, and motor outcomes at 18-month of age, with predictive features concentrated at network boundaries. This functional refinement is structurally anchored by concurrent maturation in cortical myelination and sulcal depth. Preterm birth results in distinctive topographic alterations characterized by accelerated maturation of association networks. Our work establishes a foundation for precision models of early brain development and elucidates its significance for long-term neurocognitive outcomes.

neuroscience↗

bioRxiv2025

HalluDesign: Protein Optimization and de novo Design via Iterative Structure Hallucination and Sequence design

Deep learning has revolutionized biomolecular modeling, enabling the prediction of diverse structures with atomic accuracy. However, leveraging the atomic-level precision of the structure prediction model for de novo design remains challenging. Here, we present HalluDesign, a general all-atom framework for protein optimization and de novo design, which iteratively update protein structure and sequence. HalluDesign harnesses the inherent hallucination capabilities of AlphaFold3-style structure prediction models and enables fine-tune free, forward-pass only sequence-structure co-optimization. Structure conditioning at different noise level in the structure prediction stage allows precise control over the sampling space, facilitating tasks from local and global protein optimization to de novo design. We demonstrate the versatility of this framework by optimizing suboptimal structures, rescuing previously unsuccessful designs, designing new biomolecular interactions and generating new protein structures from scratch. Experimental characterization of a diverse set of proteins--including protein binders for small molecules, a metal ion and proteins; antibody design of phosphorylation-specific peptide; and monomeric proteins--revealed high design success rates and excellent structural accuracy. Together, our comprehensive computational and experimental results highlight the broad utility of this framework. We anticipate that HalluDesign will further unlock the modeling and design potential of AlphaFold3-like models, enabling the robust creation of complex biomolecules for a wide range of biotechnological applications.

bioinformatics↗

bioRxiv2025

Distinctive Functionality of Semantic Hubs: Evidence from Semantic Dementia

Semantic cognition relies on a distributed network with multiple candidate hub regions that bind multimodal conceptual information. While the anterior temporal lobe (ATL) is widely regarded as a core semantic hub, the roles of other candidate regions--such as the fusiform gyrus (FFG) and posterior middle temporal gyrus (pMTG)--remain debated, particularly regarding verbal and non-verbal semantic processing within the same sensory modality. This study examined 33 patients with semantic dementia and 20 healthy controls using a comprehensive behavioral battery (word and picture versions of the Pyramid and Palm Trees Test and a word-picture verification task) combined with multimodal neuroimaging, including voxel-based morphometry, diffusion-weighted imaging, and resting-state fMRI. Partial correlation and commonality analyses revealed that (1) the left ATL selectively underpins abstract verbal semantic processing, (2) the left FFG contributes to general semantic processing across verbal and non-verbal stimuli, (3) and the left pMTG plays a critical role in integrating verbal and non-verbal semantic information. White matter tracts linking the left ATL and FFG to the right ATL significantly predicted semantic integration performance, underscoring the importance of inter-hemispheric structural connectivity. Functional measures in contralateral regions, including amplitude of low-frequency fluctuation (ALFF) in the right FFG and degree centrality (DC) in the right pMTG, also predicted integration outcomes, suggesting compensatory network reorganization. These findings highlight functional specialization among semantic hubs and underscore the importance of multimodal, cross-hemispheric approaches for understanding the neural architecture of semantic representation.

neuroscience↗