Biology subjects

Guo, Z.

Publications and source records attributed to Guo, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Janusein and EB Cooperate to Enhance Microtubule Plus-end Catastrophe

Microtubule (MT) plus ends are organized by end-binding (EB) proteins, yet how EB-associated factors modulate the transition from growth to catastrophe remains incompletely understood. Using spatially resolved proximity proteomics, we identified Janusein (ZC2HC1A) as a conserved, poorly characterized MT-associated protein (MAP). At low expression levels, Janusein tracked MT plus ends and reduced EB comet velocity; at higher levels, it redistributed to the MT lattice and was associated with MT bundling and widespread MT loss. Loss of Janusein resulted in spindle defects in human cells. In vitro, Janusein alone facilitated MT elongation through its C-terminal fragment, but promoted MT catastrophe through its N-terminal fragment in the presence of EB proteins. Molecular dynamics simulations and mutational analyses suggest that an N-terminal loop may perturb lateral contacts between adjacent MT protofilaments. Together, these findings identify Janusein as an unconventional MAP that functionally cooperates with EB proteins to promote MT catastrophe.

cell biology↗

bioRxiv2026

RegDesign-Bench: Benchmarking computational methods for cell-type-specific regulatory DNA design

The de novo design of regulatory DNA sequences that drive cell-type-specific gene expression could enable precise gene control in synthetic biology, cell engineering and gene therapy. Various computational methods have been developed for this task, yet systematic comparisons that guide method selection for different design objectives remain limited. Here, we introduce RegDesign-Bench, a standardized framework for evaluating cell-type-specific cis-regulatory element design through a comprehensive set of computational analyses. Among the methods tested, strong predicted activity was not consistently accompanied by cell-type-selective accessibility or prominent cell-type-associated motif signals. Similarity to reference sequence distributions also did not ensure high predicted target-cell activity or specificity. These findings demonstrate that favourable performance on individual measurements does not necessarily extend across regulatory properties and library characteristics, revealing application-dependent strengths and limitations of current design methods. Overall, RegDesign-Bench offers a general-purpose computational framework for comparing and selecting methods to design regulatory DNA that drives cell-type-specific gene expression.

genomics↗

bioRxiv2026

Cortex-wide single-cell activity mapping in freely moving mice

How the cortex supports complex, naturalistic behavior can be revealed only in freely moving animals. Although head-mounted microscopes promise access to the neural dynamics underlying such behavior, fundamental trade-offs among field of view, spatial resolution, device weight, and background contamination have prevented cortex-wide single-neuron recording, leaving distributed cortical coordination largely inaccessible. To meet these challenges, we introduce COMET (Cortex-wide Observational Miniature Epifluorescence Technique), a 3.75-g head-mounted mesoscope that integrates an aberration-controlled wide-field optical design, uniform high-efficiency excitation and single-coaxial power-and-data transmission with an end-to-end denoising and signal-extraction pipeline. This enables cortex-wide calcium imaging at single-cell resolution in freely moving mice. COMET captures activity from >15,000 layer 2/3 neurons per 5-min recording over fields of view up to 10 mm in diameter while preserving natural behavior. Benchmarking against benchtop two-photon microscopy demonstrates high spatial concordance of detected neurons and matched event-level calcium dynamics. We apply COMET to social interaction to quantify region-specific engagement and to an auditory trace fear-conditioning task that requires natural movement and behavioral expression, revealing time-ordered changes in regional firing-rate structure and functional connectivity preceding a global conditioned response. COMET provides an open, lightweight hardware-software framework for linking single-neuron activity to cortex-scale network dynamics during freely expressed behaviors under changing internal or external conditions.

neuroscience↗

bioRxiv2026

A 21-Color Spectral Flow Cytometry Panel for Comprehensive Immunophenotyping of Rat Tissues and a Companion 9-Color T-Cell Functional Assay

Although rats are crucial translational research models due to their immunological homology and surgical feasibility, the scarcity of conjugated antibodies has hampered high-dimensional immune profiling. To bridge this gap, we created a synergistic two-panel method that uses full-spectral flow cytometry: a 21-color comprehensive immunophenotyping panel and a 9-color intracellular cytokine staining (ICS) panel. The 21-color panel navigates the limited fluorophore pool and maps innate and adaptive lineages at high resolution. While it can be used to profile neutrophils and monocytes in peripheral blood it reaches its full potential in lymphoid organs, allowing for the simultaneous evaluation of tissue-resident macrophages, dendritic cells, T cell differentiation (including Tregs), and APC function. Based on this phenotypic paradigm, the 9-color ICS panel dissects effector T cell activation and Th1/Th2/Th17 cytokine production. Furthermore, we reserved the PE color during panel creation, allowing for the use of antibodies and probes with PE or comparable fluorophores in conjunction with this panel, hence increasing overall flexibility. This combination technique, designed for rat peripheral blood, spleen, and lymph nodes, combines panoramic phenotyping with functional analysis, offering an adaptable foundation for complicated tissue microenvironments in tumor immunology, rheumatology, and autoimmunity research.

immunology↗

bioRxiv2026

SEEKER: A genome-scale library-on-library screening platform for deciphering T cell recognition of antigen

Decoding which antigens activate a given T cell receptor (TCR) is a central challenge in immunology. We present SEEKER, a functional genome-scale library-on-library screening platform built on three elements: a Jurkat-derived T-APC cell (TAPCell) that combinatorially expresses one TCR and one peptide-MHC drawn from separate libraries together with an NFAT activation reporter; encapsulation of single TAPCells in a thermos-reversible hydrogel for isolated clonal expansion, so recognition is read out as intraclonal activation; and dual-asymmetric PCR that links TCR- and pMHC-encoding sequences into a heritable unit, enabling progressive hit enrichment over screening rounds. SEEKER interrogates ~10^8 TCR-pMHC combinations per run without prior knowledge. Screening joint-infiltrating CD8+ T cells from HLA-B*27+ ankylosing spondylitis patients against proteome-wide libraries validated 53 TCR-peptide pairs, uncovered extensive cross-recognition of self and common viral epitopes, and revealed highly polyreactive T cells recognizing up to 80 autoantigens, implicating virus-triggered poly-autoreactivity in multi-organ autoimmune diseases.

immunology↗

bioRxiv2026

ctDNA Release Heterogeneity in Luminal Breast Cancer Revealed by Single-Cell Multi-Omics Spatial Analysis

Backgroud Breast cancer is a leading cause of cancer-related mortality, and HR+/HER2-; is the predominant subtype. Molecular pathology, including PIK3CA and ESR1 mutation, informs prognosis and treatment selection. Circulating tumor DNA (ctDNA) offers a non-invasive approach for cancer monitoring, but its clinical utility is limited by tissue plasma discordance, reflecting heterogeneous ctDNA release. The cellular and spatial determinants of this release remain poorly understood, particularly in HR+/HER2-; subtype, where heterogeneity across subclones complicates liquid biopsy interpretation. Results To identify the cellular and spatial determinants of ctDNA release, we developed scMASTER, integrating single-cell transcriptomes and mutations, spatial transcriptomics and matched tumor and plasma DNA sequencing. In ten patients with non-metastatic HR+/HER2- breast cancer, eight recurrent malignant epithelial states showed distinct ctDNA release potential. Antigen-presentation, stress, mitosis and mesenchymal-like states showed high release. PIK3CA and ESR1 mutations were linked to distinct functional states and altered ctDNA detectability. Three spatial architectures, EMT-enriched regions, intraductal luminal progenitors and avascular hypoxic zones, showed high release. Tumor-microenvironment interactions were bidirectional: anti-tumoral immunity correlated with reduced release, whereas immunomodulatory components correlated with increased release. A stratification model based on these features identified high-risk, immunosuppressed patients with poor prognosis, validated across external cohorts. Conclusions Our study establishes a single-cell spatial framework for decoding ctDNA release heterogeneity, linking tumor states, somatic mutations, spatial architecture, and immune interactions to ctDNA release. These findings provide mechanistic insights into tissue-plasma discordance, offer a biological rationale for interpreting ctDNA dynamics, refine patient risk stratification and liquid biopsy-based monitoring in HR+/HER2-; breast cancer.

cancer biology↗

bioRxiv2026

Recursive feedback between Piezo1 conformation and membrane mechanics drives self-organization into finite clusters

Piezo1 is a major mechanosensitive ion channel through which cells convert physical force into calcium-dependent signaling programs. In living membranes, this conversion depends not only on channel activation, but also on whether Piezo1 channels remain dispersed, assemble into finite clusters, or concentrate at sites where receptor signaling and mechanical forces reorganize the membrane. How single-channel force sensing is amplified into these collective spatial states remains unknown. Here we identify a membrane-feedback mechanism that converts single-channel mechanosensing into self-organized Piezo1 clusters. Coupling channel shape to membrane-cortex elasticity reveals that neighboring channels relax shared deformation fields, generating an effective interaction with short-range attraction opposed by longer-range repulsion. As channel density or membrane tension increases, this balanced interaction shifts Piezo1 from dispersed channels into mesoscale finite clusters. Brownian-dynamics simulations reproduce experimentally observed Piezo1 cluster geometries and swelling-induced cluster growth, while comparisons across distinct cellular systems place Piezo1 organization within a common density-tension framework. Applying the same mechanism to LPS-activated macrophages shows how receptor-induced membrane reorganization locally concentrates Piezo1 above the clustering threshold. Overall, these results recast Piezo1 mechanotransduction from isolated-channel force sensing to a membrane-driven self-organization process that spatially biases force-dependent calcium signaling within cells.

biophysics↗

bioRxiv2026

Integrating structural and biological evidence to rerank ESMFold2 protein-protein interactions

Large-scale protein structure prediction enables proteome-wide protein-protein interaction (PPI) screening, but distinguishing biologically meaningful interactions from spurious interfaces remains challenging. Here, we develop a scalable framework combining fast, MSA-free ESMFold2 prediction with PAE-guided domain parsing and evidence-based reranking. Three-recycle ESMFold2-Fast achieved 57% acceptable-or-better DockQ scores on FoldBench, comparable to AlphaFold2-Multimer while substantially reducing computation. PAE-guided parsing preserved 98.1% of XL-MS cross-links within parsed domain pairs. We then developed the Structure Prediction and Omics informed Classifier (SPOC)-ESMFold2, which integrates structural features with independent biological evidence to prioritize predicted interactions. SPOC-ESMFold2 achieved an AUROC of 0.93 and AUPR of 0.90, compared with 0.87 and 0.79 for a structural-only classifier. Under a 1:128 positive-to-negative ratio, SPOC-ESMFold2 achieved 17.2% recall at 5% false-discovery rate, substantially outperforming structural confidence metrics alone. This framework enables scalable PPI screening by integrating structural plausibility with orthogonal biological evidence to prioritize candidates for experimental investigation.

bioinformatics↗

bioRxiv2026

GDNF enemas improve epithelial and immune defects in both aganglionic and ganglionic colon of Hirschsprung mice

Hirschsprung disease (HSCR) is a severe birth defect where ganglia of the enteric nervous system (ENS) are missing from distal bowel. The aganglionic segment is also characterized by increased epithelial permeability and pro-inflammatory immune activation. These problems may sequentially lead to translocation of gut microbes into the colon wall and systemic circulation, resulting in enterocolitis and sepsis. Current HSCR treatment via surgical resection of the aganglionic segment is lifesaving but not curative, often leaving patients with persistent gastrointestinal complications including recurrent risk of enterocolitis. As alternative, we are developing a regenerative medicine strategy based on in situ stimulation of tissue-resident ENS progenitors via rectal administration of the neurotrophic factor GDNF. Here, we report that GDNF-based therapy has pleiotropic gastrointestinal effects in a mouse model of short-segment HSCR, beyond its role in ENS regeneration. Interestingly, we found that these protective effects are not restricted to the aganglionic distal colon, also positively impacting the ENS-containing proximal colon. GDNF treatment reduces bacterial translocation both locally and in peripheral organs, and this is associated with recovery of the key epithelial junction proteins CLDN3, ZO1 and DSG2. Furthermore, multiparameter flow cytometry-based analysis of 55 lymphoid and 17 myeloid cell subtypes revealed that GDNF treatment has global anti-inflammatory effects, preferentially affecting innate over adaptive immunity. Overall, these findings highlight a critical role for GDNF treatment in reestablishing proper epithelial and immune cell homeostasis, offering promising therapeutic avenues not only for HSCR but also potentially for other intestinal disorders with overlapping pathophysiology.

developmental biology↗

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

Bridging Morphology and Genomics: A rapid image-based assessment of genomic admixture in the endangered gayal (Bos frontalis)

Abstract The gayal (Bos frontalis) is an endangered semi-domesticated bovine species renowned for its high-quality beef. However, its semi-feral lifestyle, ongoing habitat fragmentation, and extensive genetic introgression from sympatric local cattle have led to dramatic population decline and severe erosion of purebred genetic integrity, posing substantial challenges to its conservation and utilization. To address the urgent demand for rapid, non-invasive, and field-compatible germplasm identification, we developed an integrated artificial intelligence (AI) framework that predicts genomic admixture composition from external morphological images. We constructed a comprehensive dataset comprising 6,245 morphological images and matched genomic sequences from 52 gayals maintained at the Yunnan Provincial Gayal Conservation Farms. Following a preliminary evaluation of nine deep learning models, five were incorporated into a anatomical segment-based multi-modal pipeline, among which Inception_V3 delivered the optimal overall performance. To enhance simultaneous extraction of local fine-grained features and global structural information, we further designed an innovative HybridInceptionViT model by integrating the multi-scale Inception module with the Vision Transformer (ViT) framework. This hybrid model significantly outperformed the baseline Inception_V3, boosting the accuracy of phenotype-derived prediction against genomic admixture estimate from 69.69% to 87.87% (absolute error <15%). This study establishes a practical, low-cost "phenotype-to-genotype" tool for rapid on-site gayal germplasm screening, offering a scalable strategy for the conservation and breeding management of endangered livestock, and holds broad application prospects for agricultural and livestock production systems.

zoology↗

bioRxiv2026

Tissue-resident memory B cells augment local anti-cancer immunity via IgA

Tissue-resident memory B cells (BRM) provide powerful localized protection against microbial infection in barrier tissues. It is unknown if analogous BRM populations survey solid tumors and contribute to anti-cancer immunity. We profiled B cells from patients with colorectal cancer and cutaneous basal cell carcinoma and identified a CD69+ memory B cell population consistent with a tissue-resident phenotype. Integrative analysis of transcriptomic datasets identified an optimized signature enriched across cancer types. Tumor infiltrating BRM-like cells preferentially exhibited autoreactivity and their signature correlated with patient outcomes and response to immunotherapy. Skin and lung targeted vaccination established localized BRM that provided IgA dependent organ specific protection upon tumor challenge in murine models. These findings establish BRM as an active component of anti-cancer immunity via preferential reactivity to tumor associated self-antigens.

immunology↗

bioRxiv2026

Machine Learning Gap-Fills Missing Transporter Kinetics in Biosystems Across Scales

Understanding transporter kinetics is essential for deciphering metabolite exchanges in biosystems, particularly for cells subject to substrate gradients. Nevertheless, the prediction of transporter kinetic parameters, maximum rate per gram protein (Vmax) and Michaelis-Menten constant (Km), has not yet been tackled. Here, we developed the first compound-protein interaction machine learning model of transporter Vmax and Km, MMTKPred, which achieved R2=0.553, RMSE=1.155 mmol/hr/g Protein and R2=0.330, RMSE=0.935 mM for log10-scaled Vmax and Km prediction, respectively. Moreover, we demonstrated MMTKPreds predictive power across biosystem scales, from capturing transporter kinetics modulated by point mutations and substrate changes at the molecular level, to enabling substrate-sensitive metabolic modelling of non-model yeasts at the cellular level, and rationalizing inter-species substrate competition in co-cultures. Collectively, MMTKPred effectively models metabolite transport spanning from molecular to multi- species scales, thereby offering a computational tool for rational microbial cell factory optimization. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/735998v2_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@18e7bb6org.highwire.dtl.DTLVardef@15bec93org.highwire.dtl.DTLVardef@8ce92org.highwire.dtl.DTLVardef@31fb44_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMMTKPred, first transporter kinetics CPI model, reaches [~]1 log10 RMSE for Vmax and Km. C_LIO_LIMMTKPred captures the effects of point mutations and substrate changes on transporters. C_LIO_LIPredicted kinetics enables substrate sensitivity in metabolic flux modelling. C_LIO_LIPredicted kinetics explains inter-species substrate competition outcomes. C_LI

systems biology↗

bioRxiv2026

Phase-tuned interfacial condensates drive transcellular access

Nanocondensates occupy mesoscopic scale in both spatial scale and thermodynamic state, and the mesoscopic scale is central to structure-function conversion in living systems. However, how the dual mesoscopic properties of nanocondensates support biological function remains unclear because their small size and rapid dynamics hinder direct observation in living cells. Here we construct nanocondensates in situ at the cell-membrane interface and observe them permeating membranes within seconds, diffusing freely, exiting cells within minutes, re-entering neighbouring cells and traversing multilayered barriers. We report the first observation of this phenomenon and term it nanocondensate tunnelling. We find that nanocondensates cross membranes without membrane enclosure, preserving their wetting characteristics after passage. Theoretical and ultrastructural analyses support a transient-pore model linking this behaviour. We exploit nanocondensate tunnelling to transport small molecules, siRNA and antibodies across cellular barriers, and small molecules and siRNA across a multilayered corneal barrier, demonstrating its functional capacity for intercellular transfer. Our results suggest that nanocondensate tunnelling represents a previously undescribed mode of intercellular transfer. Nanocondensate tunnelling provides a physical basis for biologics delivery and a testable framework for investigating unresolved biological phenomena such as viral permeation.

bioengineering↗

bioRxiv2026

APOE4 Drives Uniquely Dysfunctional Human Microglial States in Alzheimer's Disease

Variation in APOE, notably the {varepsilon}4 allele, profoundly shapes risk and severity of late-onset Alzheimers disease (AD), yet how it remodels human microglial states remains unresolved. We combine spatially resolved proteomic profiling with single-nuclear multiomic analyses to define microglial organization across APOE3/3 and APOE4/4 genotypes in AD. Quantifying condition-associated variation across the cellular manifold reveals a continuous landscape of microglial states. APOE4/4 shifts cells toward terminal states marked by loss of homeostatic identity, metabolic disruption, and incomplete acquisition of disease-associated programs. We identify an APOE4/4-enriched population in AD that exhibits inflammatory signaling without effective metabolic or phagocytic engagement, localizing to niches of gliosis and senescence, and coupled to chronic stress adaptation programs. Together with evidence that APOE4/4 potentiates the activation threshold of nascent microglia, these findings establish a unified framework for human microglial state change, linking genetic risk to spatial and molecular organization of immune responses in the AD brain. Graphical Abstract.APOE4/4 in Alzheimers disease reshapes microglial fate along continuous trajectories characterized by proteomic, transcriptional, and epigenetic programs consistent with chronic stress adaptation, alongside distinct composite spatial niches comprised of astrocytic gliosis and cellular senescence. O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/733295v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@b2afa4org.highwire.dtl.DTLVardef@12978f8org.highwire.dtl.DTLVardef@1c4e46dorg.highwire.dtl.DTLVardef@170e44d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Identification and molecular characterization of a novel TYLCV isolate breaking bred-resistance to threaten tomato cultivar

Tomato yellow leaf curl virus (TYLCV) is a devastating viral pathogen threatening agricultural crops globally. In this study, we identified a novel TYLCV isolate (TYLCV-YN6244), which caused viral epidemic in resistant tomato cultivars at Yuanmo county, Yunnan Province of China. We determined the complete genome of TYLCV-YN6244 and found it encoded six viral proteins characteristic of Geminivirus. We identified its V2 protein as a potent viral suppressor of RNA silencing (VSR), and generated infectious clone of wildtype TYLCV-YN6244, or V2-defective TYLCV-YN6244 (TYLCV-YN6244-{Delta}V2) in which V2 was deleted. Both of infectious clones were capable of systemically infecting tobacco and tomato. However, TYLCV-YN6244 but not TYLCV-YN6244-{Delta}V2 could cause disease symptoms in wildtype tobacco or tomato plants, and viral accumulation was drastically reduced in plants infected with TYLCV-YN6244-{Delta}V2 compared to TYLCV-YN6244 while the efficiency of virus-derived small interfering RNAs (vsiRNAs) biogenesis was conversely increased in plants infected with TYLCV-YN6244-{Delta}V2. Surprisingly, small RNA profiling indicated that 21nt and 22nt rather than 24nt vsiRNAs were predominantly produced in tomato plants infected with either TYLCV-YN6244 or TYLCV-YN6244-{Delta}V2. Furthermore, transcriptome analyses revealed that TYLCV-YN6244 or TYLCV-YN6244-{Delta}V2 infection differentially modulated metabolism and defense-related pathways in tomato, probably underlying distinct viral pathogenicity and disease symptoms induced in plants. Overall, our research not only identified a novel pathogenic TYLCV isolate but also characterized molecular biology and host response in tomato with infectious clones firstly developed, with implications in untangling virus-host interaction for developing novel resistance in crop tomato.

Plant Biology↗

bioRxiv2026

Long-read RNA-seq resolves isoform-level and context-specific regulatory architecture of complex traits in cattle

Traditional short-read RNA-seq lacks the resolution to fully capture full-length isoforms and complex alternative splicing, leaving a "missing regulation" gap in existing molecular atlases. Here, we present a population-scale, multi-omics dissection of bovine complex traits using matched deep whole-genome sequencing (30x), long-read (ONT) and short-read RNA-seq, as well as metabolome data from 432 dairy cows across four distinct lactation stages. We expanded the bovine transcript atlas with 13,177 novel isoforms and fine-mapped 1,088,900 regulatory effects across 11 diverse molecular phenotypes. Notably, long-read mapping uncovered 606 genes with isoform expression quantitative trait loci (12.8%, eQTL) and 1,116 genes with detailed splicing QTL (sQTL) (31.8%) that were missed by conventional short-read mapping. We further showed that lactation-specific regulation was profoundly mediated by the metabolic microenvironment (46.8%) and cellular composition (4.3%). Across genome-wide associations (GWAS) of 90 bovine complex traits, isoform-level and context-specific regulatory effects captured GWAS loci missed by short-read eQTL and sQTL analyses, increasing colocalized loci from 35.2% to 60.3%. These regulatory variants also exhibited evolutionary constraints with human immune and metabolic loci. Our study establishes an invaluable resource (https://cattleblr.farmgtex.org) demonstrating that long-read transcriptomics is essential for resolving the complexity of regulatory mechanisms underlying mammalian physiology.

genetics↗

bioRxiv2026

Targeting THOC2-Mediated mRNA Export Induces PARP Inhibitor Vulnerability in DNA Repair-Competent Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. While Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit synthetic lethality in tumors with DNA repair defects, their clinical utility in HCC is hindered by the low prevalence of canonical repair gene mutations and the enhancing DNA repair capacity. Through proteomic analysis of two independent cohorts (n=260), we identified the THO complex component THOC2 as a master regulator of DNA damage response (DDR) via mRNA nuclear export control. Clinically, THOC2 overexpression predicted poor survival (HR=2.68-6.84, P<0.001) and correlated with enhanced DDR gene expression. Mechanistically, THOC2 chaperones mRNA nuclear export of DDR effectors (MDC1, PRKDC, MSH6) and proliferation drivers (TOP2A), thereby establishing a dual pro-repair/pro-growth program. Targeting this vulnerability, THOC2 knockdown induced synthetic lethality with PARPi, reducing Olaparib IC50 by up to 61% and suppressing tumor growth by 76% (P<0.001). Our study illuminates mRNA transport as a druggable DDR modulator and establishes THOC2 as both a prognostic biomarker and a therapeutic target to overcome PARPi resistance in HCC. This work pioneers a strategy to expand synthetic lethality beyond genetic defects by targeting post-transcriptional regulation.

cancer biology↗