Biology subjects

Hao, X.

Publications and source records attributed to Hao, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Early dynamics of a neutrophil interferon program drive immunotherapy resistance and limit durable anti-tumor immunity

Despite the remarkable success of immune checkpoint blockade (ICB), durable clinical benefit remains limited to a subset of patients, highlighting the need for predictive biomarkers and new therapeutic targets. Here, we investigated the early immune dynamics associated with anti-PD1 responsiveness using longitudinal single-cell transcriptomics, spatial transcriptomics, and neutrophil-specific genetic perturbations in preclinical models of triple-negative breast cancer. We identified a conserved neutrophil interferon-stimulated gene (ISG) program that emerges before overt tumor divergence and predicts resistance to anti-PD1 therapy. Successful treatment was associated with an early reduction of IFN-responsive neutrophils in both blood and tumor tissues, whereas persistent neutrophil IFN signaling correlated with therapeutic resistance. Mechanistically, genetic disruption of either type I or type II interferon signaling in neutrophils enhanced anti-PD1 efficacy and promoted durable anti-tumor immune memory. Spatial analyses further revealed an inverse association between IFN-responsive neutrophils and tertiary lymphoid structure-enriched regions during effective therapy. Together, these findings identify IFN-responsive neutrophils as early determinants of immunotherapy outcome and establish dynamic neutrophil interferon programs as candidate blood-based biomarkers and therapeutic targets for cancer immunotherapy.

cancer biology↗

bioRxiv2026

Translation sustains productive Pol II elongation through maintenance of nuclear RNA surveillance

Although transcription and translation are spatially separated in eukaryotic cells, gene expression requires coordination between the nucleus and cytoplasm. Whether translation rapidly influences nuclear transcription remains unclear. Here we show that ongoing translation sustains productive RNA polymerase II (Pol II) elongation in mouse embryonic stem cells. Translation inhibition reduces nascent transcription within 15 minutes, impairs Pol II pause release, and preferentially represses long genes before substantial loss of chromatin-associated Pol II. Unexpectedly, despite reduced transcription, nuclear RNA transiently accumulates owing impaired in RNA turnover. Mechanistically, translational arrest redistributes RNA-processing and RNA-surveillance factors from the nucleus to stalled ribosome-associated complexes in the cytoplasm, reducing their nuclear availability. Acute depletion of RNA-surveillance components phenocopies elongation defects caused by translational inhibition, particularly in long genes. Together, our findings identify ongoing translation as a regulator of nuclear RNA surveillance capacity and reveal a feedback mechanism sustaining productive Pol II elongation and nuclear RNA homeostasis.

Molecular Biology↗

bioRxiv2026

Dissociable frequency regimes in human temporal cortex integrate facial and acoustic cues during natural speech

Face-to-face communication relies on the seamless integration of visual and acoustic cues, yet the spatiotemporal principles governing how the human brain dynamically represents and combines these multisensory streams remain largely unresolved. To address this, we recorded high-density electrocorticography (ECoG) from eight participants perceiving matched audiovisual, audio-only, and video-only continuous natural Mandarin speech. Using time-frequency-resolved encoding models, we reveal complementary, frequency-dependent integration regimes across the temporal lobe. We show that the superior temporal gyrus (STG) implements a feature-selective, auditory-dominant strategy, utilizing visual input to selectively strengthen low-frequency representations of lip-reading kinematics. Conversely, the middle temporal gyrus (MTG) acts as a higher-order multisensory hub, employing a frequency-selective strategy to broadly integrate diverse facial and articulatory features. Crucially, we demonstrate that access to visual information during perception significantly improves the acoustic and lexical accuracy of neural speech decoding and re-synthesis, with the MTG driving the largest gains in linguistic intelligibility. These findings uncover the dissociable neural architectures supporting robust multisensory perception, providing critical mechanistic insights for the development of next-generation, multimodal brain-computer interfaces.

neuroscience↗

bioRxiv2025

Cyclophosphamide chemotherapy induces early p53-directed cytotoxic gene expression changes in ovarian gonadotoxicity

The alkylating chemotherapeutic cyclophosphamide (CPA) is gonadotoxic, commonly resulting in depletion of ovarian primordial follicles and leading to infertility and premature menopause in female cancer patients. However, the mechanisms underlying the early stages of CPA-induced ovarian damage are unclear, limiting our ability to prevent gonadotoxicity. This study provides a comprehensive temporal exploration of the transcriptomic profiles of ex vivo intact mouse ovaries exposed to CPA. Analyses of CPA responses from 8 to 36 hours revealed an important early role of p53 signaling. Bioinformatic analyses showed early increases in expression of specific gene clusters associated with apoptosis, DNA damage responses, and cell cycling, while expression of autophagy-associated genes was decreased. Several transcription factors, including E2F family members, likely drive early apoptosis-induced damage and p53 pathway activation. These findings provide mechanistic insight into CPA-induced ovarian toxicity, providing new avenues for the development of protective interventions.

pharmacology and toxicology↗

bioRxiv2025

DNA Methylation in Sex Chromosomes and Genes under Selection Underpins the Emergence of Sexual Size Dimorphism

Sexual size dimorphism (SSD) refers to the differences in body size between males and females. Epigenetics such as methylation contribute to shaping phenotypes, nevertheless, their role in SSD is still unclear. Here, we used Cynoglossus semilaevis, a species with larger females known as female-biased SSD, as a model to investigate the role of methylation in the emergence and regulation of SSD. Methylomes and transcriptomes were constructed in four tissues (brain, liver, muscle, and gonad) from three key life stages: juveniles (3-months post fertilization), male mature stage (1-year post fertilization; ypf), and female mature stage (3 ypf). In 1 ypf and 3 ypf females showed lower methylation, while the number of differentially methylated regions between sexes increased during the lifetime. Genes at the top of the growth hormone/insulin-like growth factor (GH/IGF) axis and hypothalamus-pituitary-gonadal axis (gh1, igf1, gnrhr2r-like, err{gamma}, etc.) showed differential methylation between sexes, consistent with sex-related differences in growth. The female-specific W chromosome showed higher methylation than the autosomes or the Z chromosome. Genes of the IGF signaling network that negatively regulate growth and located on W chromosome were hyper-methylated than their Z homologs. Furthermore, genes with a faster evolutionary rate in C. semilaevis exhibited lower methylation levels than the background genes, suggesting an important evolutionary role for DNA methylation in shaping SSD. Our results provide a comprehensive depiction of methylation regulation of SSD in vertebrates, and improve our understanding of how methylation regulation can help organisms to respond to natural selection, and allocate resources between the sexes.

developmental biology↗

bioRxiv2025

Characterization of the Mechanisms Underlying Sulfasalazine-Induced Ferroptotic Cell Death: Role of Protein Disulfide Isomerase-Mediated NOS Activation and NO Accumulation

Sulfasalazine (SAS), a clinically-utilized anti-inflammatory drug, has been shown to induce ferroptosis by inhibiting system Xc- activity, thereby causing cellular glutathione depletion. Recently, it was shown that protein disulfide isomerase (PDI) is an upstream mediator of oxidative cell death (oxytosis/ferroptosis) induced by glutamate, erastin, RSL3 and SAS. The present study aims to further characterize the detailed biochemical and cellular mechanisms of SAS-induced ferroptosis in two cell lines, i.e., H9C2 rat cardiomyocytes and BRL-3A rat hepatocytes, focusing on elucidating the critical role of PDI in mediating SAS-induced toxicity. We find that SAS can induce ferroptosis in H9C2 and BRL-3A cells, which is accompanied by a sequential increase in the buildup of cellular nitric oxide (NO), reactive oxygen species (ROS) and lipid-ROS. SAS activates PDI-mediated dimerization of the inducible NO synthase (iNOS) and cellular NO accumulation, and these effects are followed by ROS and lipid-ROS accumulation. Furthermore, SAS markedly upregulates the expression of iNOS protein in these cells. Knockdown of PDI or pharmacological inhibition of its catalytic activity each effectively suppresses SAS-induced iNOS dimerization, along with abrogation of SAS-induced accumulation of NO, ROS and lipid-ROS, and prevention of ferroptosis. On the other hand, PDI activation through the use of TrxR1 inhibitors sensitizes these cells to SAS-induced ferroptosis. These experimental findings provide further experimental support for a pivotal role of PDI in SAS-induced cytotoxicity through the activation of the PDI-NOS-NO axis, which then leads to cellular ROS and lipid-ROS accumulation, and ultimately induction of oxidative cell death.

biochemistry↗

bioRxiv2025

Implementation of an adaptive-optics assisted isoSTED nanoscope

The highest level of three-dimensional (3D) resolution in stimulated emission depletion (STED) nanoscopy involves harnessing a 4Pi architecture using two opposing objectives. This protocol describes the construction and alignment of a 4Pi-STED nanoscope, commonly referred to as an isoSTED nanoscope. It guides interested researchers through assembling optomechanical components, configuring electronic and control devices, aligning the optical beam path, and assessing the instruments performance. Designed for adept optical instrument builders, this protocol offers a detailed roadmap for constructing an isoSTED nanoscope with adaptive optics (AO) in approximately 12 months. With this finely calibrated instrument, researchers can achieve 3D biological images with isotropic sub-50-nm resolution in thick samples up to 35 {micro}m in depth.

bioengineering↗

bioRxiv2025

Genetic association between posterior parietal cortex and intelligence

The identification of intelligence-associated loci raises questions for functional association of brain regions and for different intelligence concepts of either a general capability or discrete abilities. By generating single-nucleus transcriptomic atlas of mouse posterior parietal cortex (PPC), which is implicated in quantification behavior, we find that human intelligence-associated gene homologs are significantly enriched in certain specific neurons within the PPC. We also find 73% of the human intelligence gene homologs are highly enriched in PPC. In addition to PPC, several regions at different locations, not cortex next to PPC, are also significantly associated with intelligence genes. The separate locations of these cortex regions and their regional-specific expressed intelligence genes raise the possibility for discrete intelligence capabilities. Animal behavior analysis reveals that mutations for two top intelligence-associated genes with specific expression in either PPC or entorhinal cortex (ENT) affect quantification or learning and memory, respectively. Finally, five patients with PPC resection in the left hemisphere also display quantification defects, but not other cognitive abilities. Together, our studies provide the first genetic and functional evidence for the involvement of PPC in intelligence. Our data also support the model of multiple intelligence over a general capability for intelligence.

genetics↗

bioRxiv2025

Early gonadotoxic effects of cyclophosphamide on the prepubertal testis and the feasibility of reducing toxicity through combined antioxidant therapy

One Sentence SummaryEarly gonadotoxic effects of cyclophosphamide (CPA) on prepubertal testes were identified, with molecular damage detectable within 16 hours and histological changes by 32 hours, while antioxidant co-treatment showed potential for protection. CPA induces early molecular damage in prepubertal testes, with protective antioxidant effects observed within the first 16 hours, highlighting the potential for mitigating testicular toxicity without compromising anticancer efficacy. This study demonstrates that CPA-induced testicular toxicity in prepubertal mice occurs early at the transcriptional level, with antioxidants showing protective effects, underscoring the need for further research on safe and effective protective strategies. At high doses, alkylating drugs toxicity leads to testicular atrophy and spermatogonial stem cells depletion, rendering survivors of childhood cancers infertile, as a recognized late effect. We used in-vivo experimental models to identify early gonadotoxic effects induced by cyclophosphamide (CPA) on prepubertal testes and to investigate if a treatment with antioxidants could reduce that toxicity. Effects were estimated by histological evaluation and whole-transcriptome RNA-sequencing (RNA-seq) of sacrificed animals at 8 hours intervals. Sixty pre-pubertal mice were randomly assigned to 1) intraperitoneal treatment with 100 mg/Kg CPA; 2) CPA in addition to antioxidants (AO) L-Carnitine (LC 50mg/kg) and N-acetyl cysteine (NAC 50); 3) AO alone; 4) control receiving saline solution (Ctrl) (N=15 for each group). Three additional animals were used for baseline assessments. On histology, changes were evident at 32 hours post-treatment. However, RNA-seq analyses revealed that the molecular impact of CPA occurred early within the first 16 hours of exposure to the drug, and that protective effects of AO in combined CPA therapy (CPA+AO) could be achieved during that period. This study demonstrates side effects of CPA on testicular tissue in the first 48 hours on transcriptional scale. Our findings indicate that early administration of AO can mitigate CPA-induced testicular damage in-vivo and suggest that protective treatments against prepubertal testis damage could be developed. However, such protective treatment should not interfere with the desired cytotoxic effects on the malignancies, thus further research is needed to evaluate the timing and how safe administration of the protectant could be achieved for medical treatment.

pharmacology and toxicology↗

bioRxiv2024

A 36-base hairpin within lncRNA DRAIC, which is modulated by alternative splicing, interacts with the IKKα coiled-coil domain and inhibits NF-kB and tumor cell phenotypes

A tumor-suppressive long noncoding RNA (lncRNA) DRAIC (down-regulated RNA in cancers) inhibits NF-{kappa}B activity and physically interacts with IKK, a kinase component of the IKK complex, in several cancer types. Here we explore the precise molecular mechanism involved in this interaction and suppression. Using SHAPE-MaP, we identified a 36-nucleotide hairpin (A+B) within DRAIC that is necessary and sufficient for its anti-oncogenic function. RNA immunoprecipitation (RIP) and Electrophoretic mobility shift assays (EMSA) confirmed this hairpin physically interacts with the coiled coil domain of IKK. A+B RNA has a high binding affinity (KD [~]1-7 nM) to the coiled-coil domain of IKK. The binding of A+B disrupts the dimerization of NEMO and IKK coiled-coil domains, a critical step for IKK action. Consistent with this, A+B inhibits the phosphorylation of the NF-{kappa}B inhibitor I{kappa}B and suppresses NF-{kappa}B activity. Publicly available tumor RNAseq data revealed that alternative splicing modulates the presence of this critical hairpin: the inclusion of exon 4a (encoding one side of the A+B hairpin) in lung tumors correlates with reduced NF-{kappa}B activity. By demonstrating that the A+B hairpin is both necessary and sufficient to inhibit IKK and oncogenic phenotypes, this study underscores the centrality of IKK interaction and NF-{kappa}B inhibition in DRAIC-mediated cancer suppression and indicates that the activity of this lncRNA is regulated by alternative splicing. This study also reveals the first example of a short RNA disrupting coiled-coil dimerization, offering a new approach to disrupt such dimerization in cancer biology.

molecular biology↗

bioRxiv2024

Chromosome-scale assembly and annotation of the wildwheat relative Aegilops comosa

Wild relatives of wheat are valuable sources for enhancing the genetic diversity of common wheat. Aegilops comosa, an annual diploid species with an MM genome constitution, possesses numerous agronomically valuable traits that can be exploited for wheat improvement. In this study, we report a chromosome-level genome assembly of Ae. comosa accession PI 551049, generated using PacBio high-fidelity (HiFi) reads and high-throughput chromosome conformation capture (Hi-C) data. The assembly spans 4.47 Gb, featuring a contig N50 of 23.59 Mb and a scaffold N50 of 619.05 Mb. A total of 39,063 gene models were annotated through a combination of homoeologous proteins, Iso-Seq, and RNA-Seq data. Comparative genome analysis revealed a terminal intrachromosomal translocation in chromosome 2M of Ae. comosa (and Ae. umbellulata) compared to its homoeologous chromosomes in other diploid wheat species. Phylogenetic analysis showed a close relationship between Ae. comosa and Ae. umbellulata. This newly constructed reference genome of Ae. comosa will serve as an important genomic resource for comparative genomic studies and the cloning of agriculturally important genes.

genomics↗

bioRxiv2024

Manipulation of the brown glume and internode 1 gene leads to alterations in lignified tissue coloration, lignification, and pathogen resistance in wheat

Lignin is a crucial component of the cell wall, providing mechanical support and protection against biotic and abiotic stresses. However, little is known about wheat lignin-related mutants and their roles in pathogen defense. In this study, we identified an ethyl methanesulfonate (EMS)-derived Aegilops tauschii mutant named brown glume and internode 1 (bgi1), which exhibits reddish-brown pigmentation in various tissues, including internodes, spikes, and glumes. Using map-based cloning and single nucleotide polymorphism (SNP) analysis, we identified AET6Gv20438400 (BGI1) as the leading candidate gene, encoding the TaCAD1 protein. The mutation occurred in the splice acceptor site of the first intron, resulting in a premature stop codon in BGI1. We validated the function of BGI1 using loss-of-function EMS and gene editing knockout mutants, both of which displayed reddish-brown pigmentation in lignified tissues. BGI1 knockout mutants exhibited reduced lignin content and shearing force relative to wild type, while BGI1 overexpression transgenic plants showed increased lignin content and enhanced disease resistance against common root rot and Fusarium crown rot. We confirmed that BGI1 exhibits CAD activity both in vitro and in vivo, playing an important role in lignin biosynthesis. BGI1 was highly expressed in the stem and spike and localized in the cytoplasm. Transcriptome analysis revealed the regulatory networks associated with BGI1. Finally, we demonstrated that BGI1 interacts with TaPYL-1D, potentially involved in the abscisic acid signaling pathway. The identification and functional characterization of BGI1 significantly advance our understanding of CAD proteins in lignin biosynthesis and plant defense against pathogen infection in wheat.

plant biology↗

bioRxiv2024

Co-transcriptional RNA processing boosts zygotic gene activation

Transcription decodes protein-coding genes and interprets regulatory information embedded in the genome by generating RNA. In eukaryotes, gene transcription is coupled with RNA processing via the carboxyl terminal domain (CTD) of RNA polymerase (Pol) II, which enhances messenger RNA (mRNA) production. We propose that co-transcriptional RNA processing is essential for zygotic gene activation (ZGA), transitioning the transcription program from noncoding to protein-coding after fertilization. Truncating the CTD in mouse cells disrupts this coupling, halting global mRNA synthesis and increasing noncoding RNA (ncRNA) levels through enhanced intergenic transcription and RNA stabilization. CTD truncation also triggers epigenetic reprogramming and nuclear reorganization towards totipotency, resembling early cleavage embryos. Mechanistically, the CTD restrains nonproductive polymerase activity in noncoding sequences, while at protein-coding genes requiring RNA processing, it promotes elongation by facilitating polymerase promoter-proximal pausing, transcription directionality, and velocity. Longer CTD lengths enhance gene activity, likely evolving to accommodate the increasing noncoding sequences in mammalian genomes.

developmental biology↗

bioRxiv2024

Organoid Modeling and Single-Cell Profiling Uncover the Migration Mechanism of Smooth Muscle Cells in Moyamoya Disease

Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive occlusion of the intracranial arteries, resulting in severe ischemic or hemorrhagic stroke. The main characteristic of the affected vessels in MMD is arterial intimal thickening. However, there are no in vitro or in vivo models that can mimic its vascular characteristics. Moreover, the mechanisms underlying the intimal thickening remain unexplained. Here, we generated vascular organoids by differentiating human induced pluripotent stem cell derived from the peripheral blood of MMD patients, thereby creating an organoid model reflecting both the genetic background and characteristics of the affected vessels. Through single-cell sequencing, we found the increased vascular smooth muscle cell (VSMC) proportion and its functional abnormalities in MMD organoids. Proteomics and RNA sequencing identified abnormal TUBA4A and TUBB4B overexpression in both the organoids and patient serum. The following in vitro experiments demonstrated that TUBA4A and TUBB4B promote the contractile-to-synthetic phenotypic switching, migration and proliferation in VSMC. Further experiments identified the GJA1-mediated PI3K/AKT/KLF4 pathway as a key regulating pathway of these phenotypic changes in VSMCs. Our findings demonstrate that the abnormal expression of TUBA4A and TUBB4B in VSMC might be a significant contributor to the intimal thickening in the affected vessels of MMD.

cell biology↗

bioRxiv2024

Survival of hepatocytes from executioner caspase activation promotes liver regeneration by enhancing JAK/STAT3 activity

Activation of executioner caspases, which is a key step in the apoptotic process, has been reported to promote tissue regeneration by sending pro-proliferation signals to the surrounding cells. However, whether executioner caspase activation (ECA) has cell-autonomous effect on tissue regeneration is not clear. Here, by generating transgenic mice carrying a lineage tracing system for cells that have experienced ECA, we demonstrate that transient ECA occurs in hepatocytes during liver regeneration after partial hepatectomy (PHx) or carbon tetrachloride (CCl4) treatment. Instead of committing apoptotic cell death, the majority of hepatocytes with ECA survive and proliferate to contribute to liver regeneration. Interestingly, inhibition of ECA in livers results in reduced hepatocyte proliferation and impaired regeneration, whereas increasing ECA to a level sufficient to kill hepatocytes also impedes regeneration, suggesting that ECA needs to be precisely controlled during liver regeneration. Mechanistic studies show that ECA promotes hepatocyte proliferation during regeneration through enhancing JAK/STAT3 activity. Our work reveals an essential role of survival of hepatocytes from ECA in liver regeneration.

developmental biology↗

bioRxiv2024

Boundaries in the eyes: measure event segmentation during naturalistic video watching using eye tracking

During naturalistic information processing, individuals spontaneously segment their continuous experiences into discrete events, a phenomenon known as event segmentation. Traditional methods for assessing this process, which include subjective reports and neuroimaging techniques, often disrupt real-time segmentation or are costly and time intensive. Our study investigated the potential of measuring event segmentation by recording and analyzing eye movements while participants view naturalistic videos. We collected eye movement data from healthy young adults as they watched commercial films (N=104), or online Science, Technology, Engineering, and Mathematics (STEM) educational courses (N=44). We analyzed changes in pupil size and eye movement speed near event boundaries and employed inter-subject correlation analysis (ISC) and hidden Markov models (HMM) to identify patterns indicative of event segmentation. We observed that both the speed of eye movements and pupil size dynamically responded to event boundaries, exhibiting heightened sensitivity to high-strength boundaries. Our analyses further revealed that event boundaries synchronized eye movements across participants. These boundaries, can be effectively identified by HMM, yielded higher within-event similarity values and aligned with human-annotated boundaries. Importantly, HMM-based event segmentation metrics responded to experimental manipulations and predicted learning outcomes. This study provided a comprehensive computational framework for measuring event segmentation using eye-tracking. With the widespread accessibility of low-cost eye-tracking devices, the ability to measure event segmentation from eye movement data promises to deepen our understanding of this process in diverse real-world settings.

neuroscience↗

bioRxiv2024

Behavioral and Eye-Tracking Evidence for Disrupted Event Segmentation during Continuous Memory Encoding Due to Short Video Watching

The proliferation of short-video platforms prompts critical investigation of their effects on human cognitive functions. We hypothesized that the frequent, user-driven content shifts inherent to short-video watching impair event segmentation--a cognitive process critical for organizing continuous experience into discrete, episodic memory. To investigate this hypothesis, we combined behavioral memory tasks, eye-tracking, and self-report questionnaires. Study 1 (N=113) revealed that exposure to randomly selected short videos impaired subsequent memory for continuous movies. This impairment was not observed following exposure to personalized short videos, nor was it present in trial-based static image encoding tasks (Study2, N=60), suggesting a selective disruption of continuous memory encoding. Intersubject correlation (ISC) analysis of eye movements revealed decreased synchronization at event boundaries during movie watching after exposure to random short videos. Furthermore, the Hidden Markov Model (HMM) analysis indicated that this exposure led to more fragmented event segmentation during continuous memory encoding. In contrast, while pupil size and gaze moving speed were sensitive to event boundaries, these metrics were not modulated by prior short video watching, indicating the disruption is specific to the segmentation process itself and not to lower-level boundary detection. Collectively, these findings demonstrate a negative impact of certain short video watching habits on event segmentation and subsequent memory, underscoring the powerful role of platform algorithms in shaping human cognition.

neuroscience↗

bioRxiv2024

Genomic and transcriptomic profiles influence on brain morphology and their interactions with pain sensitivity

Pain sensitivity varies widely among individuals and is influenced by a complex interplay of multi-omics factors, including genetic variations, gene expression, and brain morphology. While previous studies have identified associations between pain sensitivity and brain morphology, the exact mechanisms by which genetic profiles interact with brain structure to influence individual pain sensitivity remain unclear. In this study, we used aggregated datasets, including magnetic resonance imaging (MRI) and single nucleotide polymorphism (SNP) genotypes from 432 healthy participants, along with gene expression data from the Allen Human Brain Atlas (AHBA), to explore this multi-omics interplay. We first measured individual pain thresholds using laser stimuli and discovered structural brain differences between high and low pain sensitivity groups. We then identified two key gene sets with polarized expression patterns linked to brain morphology variations, enriched in functions related to ion channels and transmembrane transporter activities. Further statistical and mediation analyses revealed specific SNPs from ECM1, SLC24A2, and SCN9A genes that influence pain sensitivity, mediated through brain morphological changes in multiple basal ganglia regions. Our findings suggested that these SNPs not only affect brain structure but also modulate how individuals pain perception. Finally, we proposed an interpretation model integrating genomic, transcriptomic, and neuroimaging data, providing a detailed framework that illustrates the multi-omics contributions to individual difference in pain sensitivity. This study advances our understanding of how genetic and brain structural factors combine to shape pain perception, offering potential targets for personalized pain management strategies.

bioinformatics↗