Biology subjects

Yang, X.

Publications and source records attributed to Yang, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Glioblastoma Hijacks Astrocyte Ribosomes to Feul Malignancy through Translatome Reprogramming

Cancer cells demand elevated protein synthesis, yet whether they directly requisition ribosomes from microenvironmental host cells remains unknown. Here, utilizing in vivo and in vitro ribosome tracing, we show that glioblastoma (GBM) cells hijack ribosomes from surrounding astrocytes via tunneling nanotube-like structures. This transfer supports GBM malignancy in both murine and patient derived models. Single cell RNA sequencing along with whole cell and cell source traceable ribosome profiling reveal that transferred ribosomes are translationally active and selectively reprogram the tumor translatome, prioritizing cell-cycle genes and driving interferon-response-mediated immune evasion. Through a genome wide CRISPR screen, we identify INTS12 as a critical mediator of ribosome transfer. Genetic inactivation or AAV-mediated knockdown of INTS12 impairs ribosome uptake, curbs translation and proliferation, remodels the immunosuppressive landscape, and extends survival in orthotopic models. Our study uncovers a parasitic translation-support mechanism in GBM, establishing INTS12 as a therapeutic vulnerability to disrupt ribosome transfer.

cancer biology↗

bioRxiv2026

Integrative drug discovery for Parkinson disease with DIMER

Translating Parkinson disease (PD) genetics into therapeutic candidates requires approaches that account for interconnected disease mechanisms and their cellular context. Here we present DIMER (Direct and Indirect Module Evaluation for Repurposing and screening), a framework that connects network-based drug repurposing and target-directed virtual screening through shared disease-associated gene sets. Applying DIMER to PD, we integrated genetic risk and mechanism-associated gene sets with drug-target interactions, disease transcriptomes, and single nucleus expression profiles. Network analysis identified 423 repurposing candidates, with 71% of qualifying drug-gene set associations arising through targets outside the corresponding disease gene set. Transcriptional reversal analysis and cell type-resolved networks further distinguished candidates by their predicted effects on disease-associated expression and their cellular context, while target-set separation nominated potentially complementary drug combinations. For target-directed virtual screening, DIMER adapted a pretrained compound-protein interaction model to screening library chemistry and incorporated known-ligand similarity into compound ranking. Library adaptation improved compound-target pair classification performance, whereas ligand-informed ranking increased early enrichment of known active compounds. Consensus screening of 1.82 million compounds against seven PD-associated proteins yielded a shortlist of 22 compounds supported by at least five ranking runs. In a complementary experimental evaluation, four repurposing candidates (polydatin, fedratinib, sorafenib and venlafaxine) attenuated the loss of dopamine neuron marker signals in human midbrain organoids exposed to 6-hydroxydopamine. Together, these findings establish DIMER as a framework for translating disease-associated genes into pharmacological hypotheses and prioritizing candidates for experimental testing.

neuroscience↗

bioRxiv2026

Screening and evaluation of medicine food homology herbal combinations for ameliorating chemotherapy induced ovarian aging under an integrated multi-strategy framework

Abstract Background: Ovarian aging poses a serious threat to women's reproductive health. Medicine food homology (MFH) herbs, owing to their favorable safety profile and suitability for long-term use, have become important interventional resources. However, conventional formula screening relies largely on empirical statistics and lacks mechanistic evidence and a systematic screening strategy. Methods: In this study, we integrated single cell transcriptomic analysis, human use evidence mining, UPLC/Q TOF MS chemical profiling and pretrained protein molecular representation models to establish a multi strategy framework for the discovery of MFH herbal combinations. Single cell transcriptomic datasets related to ovarian aging from the GEO database were analyzed to identify key pathological processes and candidate targets. High-frequency MFH herbs were selected by mining classical prescriptions and clinical literature. By comparing six protein molecular pretrained representation combinations, ESM T5 was identified for compound target affinity prediction and validated by molecular dynamics simulation and surface plasmon resonance (SPR) assays, ultimately identifying the Astragalus ginseng (Huangqi Renshen) herb pair (HXF) as the core candidate. Functional expression validation of key targets was performed, and the efficacy of HXF and the expression of related molecules were verified in a D gal induced KGN granulosa cell senescence model and a cyclophosphamide-induced rat model of diminished ovarian function. Results: Single cell analysis revealed that ovarian aging was characterized by impaired steroidogenesis, enhanced MDK NCL communication between granulosa cells and immune cells, and extracellular matrix remodeling, with CYP19A1, SERPINE1 and MDK as key targets. By further integrating human-use evidence mining and UPLC/Q TOF MS compound annotation, an MFH compound library comprising 712 molecules was established. ESM T5 prediction, molecular dynamics (MD) simulation and SPR assays confirmed that multiple constituents of Astragalus and ginseng exhibited favorable binding activity toward key targets. At the cellular level, knockdown of MDK or SERPINE1 attenuated the senescence phenotype, whereas knockdown of CYP19A1 aggravated it. In vitro and in vivo experiments demonstrated that Astragalus ginseng ameliorated granulosa cell senescence and diminished ovarian function in rats, restored CYP19A1 related steroidogenesis, downregulated inflammation- and matrix remodeling related molecules such as SERPINE1 and IL18, and reduced MDK NCL colocalization signals. Conclusion: This study established a multi-strategy screening framework integrating disease mechanism decoding, human use evidence constraints and pretrained model prediction, and identified Astragalus ginseng as a candidate herb pair for ameliorating ovarian aging. Its effects may be associated with promoting steroidogenesis, suppressing SERPINE1/IL18 related inflammation and matrix remodeling, and modulating MDK NCL signaling. These findings provide a strategic reference for the mechanism oriented discovery of MFH herbal combinations.

pharmacology and toxicology↗

bioRxiv2026

Pulmonary colonization of Candida albicans drives breast cancer lung metastasis via candidalysin

The intratumoral mycobiome is emerging as a key modulator of cancer progression, with specific fungal taxa as potential biomarkers. However, whether and how mycobiomes colonizing distant organs contribute to tumor evolution remains largely unexplored. Here, we identify selective enrichment of Candida albicans in breast cancer lung metastases. Mechanistically, the fungal virulence factor candidalysin activates pulmonary mast cells, which release chemotactic mediators that expand immunosuppressive populations and suppress cytotoxic lymphocyte activity, remodeling the lung into a metastasis-permissive microenvironment. Analysis of clinical isolates and isogenic mutants further demonstrates that candidalysin secretion levels dictate metastasis-promoting potential. Informed by these findings, we developed a combination regimen that concurrently eliminates fungal colonization, stabilizes mast cells, and reverses the immunosuppressive microenvironment, thereby significantly curtailing metastatic progression. Collectively, our study establishes pulmonary C. albicans colonization as a driver of breast cancer lung metastasis and provides a mechanistic framework for targeting mycobiome-host interactions in metastatic disease.

cancer biology↗

bioRxiv2026

Heat-dependent engagement of a buried mitophagy motif in prohibitin 2

Mitophagy receptors are generally switched on by upstream enzymes rather than by the receptor itself. Whether a receptor can instead respond directly to a physical stimulus has not been established. Here we show that a second LC3-interacting region (LIR) in prohibitin 2 (PHB2) is regulated by temperature. It lies in a marginally stable helix that holds its two anchor residues about 5 angstrom apart, whereas a bound LIR spans about 9 angstrom. Replica-scaling simulations showed that this helix, but not a matched control from the same protein under identical scaling, samples that geometry; purified PHB2 bound ATG8-family proteins only at 313 K and above. Substitutions designed from this geometry to stabilise (K253A/R255A) or destabilise (I254G) the helix altered binding, mitochondrial recruitment and respiration in PHB2-null cardiomyocytes. Mice carrying the stabilising substitutions in cardiomyocytes sustained greater cardiac injury during heat stroke despite matched thermal load and comparable systemic injury. Motif accessibility may therefore be a regulated variable rather than a fixed property of a fold.

molecular biology↗

bioRxiv2026

Acetylation of NDUFA13 at K7 Senses OXPHOS Dysfunction to Disrupt Prohibitin Scaffolds and Drive Cristae Remodelling in Heart Failure

Mitochondrial cristae disintegration is a hallmark of heart failure, yet how oxidative phosphorylation (OXPHOS) dysfunction triggers this structural collapse remains unclear. Here we identify acetylation of the complex I subunit NDUFA13 at lysine 7 (K7) as a metabolic sensor coupling OXPHOS dysfunction to cristae remodelling. OXPHOS inhibition drove NDUFA13-K7 hyperacetylation, inducing conformational compaction and translocation to the intermembrane space. Acetylated NDUFA13 competitively engaged PHB2 through its coiled-coil domain, displacing PHB1 and disassembling prohibitin scaffolds. The acetylation-mimetic NDUFA13-K7Q induced cristae fragmentation in vitro, and cardiomyocyte-specific K7Q knock-in mice showed accelerated mortality and cristae loss under pressure overload, accompanied by impaired TCA cycle flux, defective fatty acid oxidation and selective depletion of polyunsaturated cardiolipins. These findings establish NDUFA13-K7 acetylation as a reversible switch converting bioenergetic failure into pathological cristae remodelling and metabolic reprogramming, highlighting therapeutic potential for targeted deacetylation.

cell biology↗

bioRxiv2026

A light-responsive lipid nanoparticle platform delivering Cas9 RNP for VEGFA editing suppresses choroidal neovascularisation

Choroidal neovascularisation (CNV) is a major cause of irreversible vision loss. Conventional anti-VEGF therapies for CNV often require repeated intravitreal injections, imposing substantial treatment burden and cumulative injection-related risk. Genome editing to disrupt VEGFA could provide durable suppression, potentially from a single administration. However, durability depends on permanently disrupting the target in a well-controlled way, as unrestricted VEGFA loss can cause choriocapillaris atrophy and compromise retinal function. This represents a major safety barrier to clinical translation. In this study, we developed lipid-based nanoparticles to release Cas9/sgRNA ribonucleoprotein (RNP) complexes under light illumination, enabling light-controlled editing of the VEGFA gene. The nanoparticles had a mean hydrodynamic diameter of approximately 130 nm with low polydispersity (0.296) and high sgRNA encapsulation efficiency (90.33%). In human retinal pigment epithelial cells, light exposure increased the extent of VEGFA disruption relative to the non-illuminated condition, as confirmed by targeted next-generation sequencing, with corresponding reductions in VEGFA mRNA and protein expression. Following a single intravitreal injection in a laser-induced rat CNV model, the nanoparticles combined with light illumination significantly reduced vascular leakage and CNV-associated structural abnormalities compared with both vehicle and non-illuminated controls, and ocular safety assessment revealed no apparent nanoparticle-related structural abnormalities in the retina. This study provides a foundation for spatially controlled VEGFA genome editing as a potential therapeutic strategy for VEGFA-driven macular neovascular disease.

bioengineering↗

bioRxiv2026

The effects of DNA repair factor-Cas9 fusions on homing drive performance

CRISPR-based homing gene drives achieve super-Mendelian inheritance by converting wild-type alleles into drive alleles through homology-directed repair (HDR). However, competing end-joining repair can generate resistance alleles that limit drive spread. Although fusing Cas9 to DNA repair-associated proteins has improved HDR in conventional genome editing systems, its effectiveness in gene drives remains unclear. Here, we systematically evaluated in Drosophila melanogaster eight Cas9 fusion constructs previously reported to improve HDR in other systems. Although none of the fusion constructs significantly increased HDR-associated signals in S2 cells, several candidates retained relatively high activity comparable to standard Cas9. These candidates were then tested in vivo across multiple split drive systems, regulatory elements, target loci, and parental sexes. Cas9-POLD3 significantly increased female drive inheritance in contexts with low baseline efficiency or substantial nonfunctional resistance formation, likely by increasing effective cutting rate and potentially also by biasing repair outcomes toward drive conversion. Cas9-Geminin degron generally maintained germline drive performance while reducing embryo resistance. Together, these findings identify Cas9-POLD3 and Cas9-Geminin degron as complementary, context-specific tools for enhancing drive conversion and limiting embryo resistance, respectively. These results highlight the importance of matching fusion modules to the regulatory and genetic context of individual drive systems.

genetics↗

bioRxiv2026

Ascorbate is a physiological tumor suppressor metabolite in leukemia

Accumulation of oncometabolites promotes tumorigenesis, but it is not known if there are naturally occurring tumor suppressor metabolites whose deficiency within cancer-initiating cells causes cancer. Many leukemia patients are ascorbate deficient. Here we show that hematopoietic-specific ascorbate depletion in mice is sufficient to cause or promote leukemogenesis. Hematopoietic-specific ascorbate depletion promoted leukemogenesis by acting within leukemia initiating cells. Ascorbate depletion in myeloid leukemia expanded plasmacytoid dendritic cells, an effect mediated by the ascorbate molecular targets TET2 and TET3. Leukemia cells accumulated ascorbate as part of a tumor suppressor response to neoplastic proliferation that limited progression but depleted circulating ascorbate. Ascorbate restoration in mice with established leukemias extended survival. Hematopoietic-specific ascorbate depletion caused leukemia in collaboration with TET2 loss and was sufficient to cause leukemia with high penetrance even in the absence of other engineered mutations. These results identify ascorbate as a physiological tumor suppressor metabolite in blood cancers.

cancer biology↗

bioRxiv2026

Central platelet-rich plasma administration promotes weight loss in diet-induced obese mice

Aims: Platelet-rich plasma (PRP) contains diverse bioactive factors, but its potential role in central regulation of energy balance remains unexplored. This study investigated whether central PRP administration alters metabolic homeostasis in diet-induced obese (DIO) mice and examined associated hypothalamic responses under obese and inflammatory conditions. Materials and Methods: PRP was administered intracerebroventricularly in mouse models of DIO and lipopolysaccharide (LPS)-induced systemic inflammation. Body weight, food intake, energy metabolism, and adiposity were assessed alongside hypothalamic microglial morphology and transcriptomic profiling. Results: A single intracerebroventricular PRP injection reduced body weight in DIO mice, with the effect persisting throughout the 7-day observation period. PRP also decreased cumulative food intake, relative gonadal white adipose tissue weight, and fasting glucose, accompanied by increased energy expenditure, oxygen consumption, fat utilization, and physical activity. In both DIO and LPS-treated mice, PRP reduced IBA1-positive area per microglial cell in the arcuate nucleus without altering microglial number. Hypothalamic RNA sequencing revealed changes in immune and metabolic signaling, extracellular matrix organization, and growth-related pathways, suggesting a complex transcriptional response rather than uniform suppression of inflammation. Conclusions: A single central PRP administration induces sustained weight loss and favorable metabolic changes in DIO mice, accompanied by region-specific hypothalamic microglial and transcriptional responses. These findings identify central PRP as a potential modulator of energy balance and provide a basis for investigating its active components and underlying mechanisms.

neuroscience↗

bioRxiv2026

Live imaging reveals oocyte membrane pre-remodeling forming permissive space for asymmetric division

Abstract Successful oocyte maturation requires first polar body (PB1) extrusion, yet how the oocyte prepares for this asymmetric event remains unclear. Live membrane imaging of mouse oocytes reveals pronounced regional heterogeneity in plasma-membrane dynamics, generating an early polarized pattern across the surface. Whereas most of the oocyte surface and its microvilli remain relatively stable, a discrete membrane domain collapses and retracts around germinal vesicle breakdown (GVBD), separating from the zona pellucida to establish a pre-extrusion space (PES). Transient oocyte comb-like protrusions arise within the PES and subsequently collapse, converting the protrusion-filled region into an open cavity before PB1 extrusion. Mechanistically, early ERK28 dependent dissociation of the cortical scaffold ZO-1 is required for this space to form. ERK2 phosphorylates ZO-1, suppresses its phase separation, and promotes its removal from the cortex. Blocking MEK-ERK signaling prevents ZO-1 dissociation, abolishes pre-extrusion space formation, and impairs PB1 extrusion, whereas ERK activation restores these events in aged oocytes. Together, our findings identify a membrane collapse-based pre-remodeling mechanism that licenses PB1 extrusion and reveal ERK-ZO-1 signaling as a key regulator of oocyte maturation.

cell biology↗

bioRxiv2026

Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior

Branched-chain amino acid metabolism is linked to neurodevelopmental disorders, but whether a defined amino acid directly modulates cortical receptor signaling to control behavior is unknown. Here, we show that valine is uniquely required for sociability through medial prefrontal cortex (mPFC) circuitry. Partial dietary valine restriction, but not comparable leucine or isoleucine restriction, or mPFC-restricted acceleration of BCAA catabolism through Bckdk loss, disrupts social interaction, and local valine supplementation rescues behavior. LiP-SMap, surface plasmon resonance, cryo-EM, and mutagenesis identify metabotropic glutamate receptor 5 (mGluR5) as a direct valine target and reveal a valine-selective allosteric pocket distinct from the glutamate site. Valine is signaling-biased: it drives {beta}-arrestin-linked output yet has little standalone Gq efficacy, instead potentiating glutamate-evoked mGluR5 signaling to recruit endocannabinoid/CB1 feedback, gate inhibitory transmission, and preserve mPFC-dependent social behavior. Together, these findings identify valine as a diet-derived allosteric ligand that links amino acid availability to cortical circuit control of social behavior.

neuroscience↗

bioRxiv2026

Venetoclax Resistance Creates Canonical Pyroptosis Vulnerability in AML

Venetoclax has transformed acute myeloid leukemia (AML) therapy, yet resistance is almost inevitable. Its diverse, often difficult-to-target drivers frequently converge on monocytic differentiation, a state that survives on MCL1 rather than BCL2. Here, we show that the very cells that escape BCL2 inhibition retain the canonical pyroptosis machinery of normal monocytes. Across 15 bulk and 4 single-cell cohorts, the canonical pyroptosis program was enriched in monocytic AML and monocytic leukemia stem cells, correlated with venetoclax resistance, and associated with inferior survival specifically after venetoclax-based therapy. In 24 cell lines and 142 patient specimens, both DPP8/9 inhibition by Val-boroPro and NLRP3 activation by lipopolysaccharide (LPS) plus nigericin preferentially killed monocytic AML cells through GSDMD-mediated pyroptosis, largely sparing non-monocytic AML and lymphoid leukemias. Venetoclax preferentially depleted primitive AML blasts but enriched a monocytic residuum vulnerable to canonical pyroptosis; combining venetoclax with Val-boroPro achieved deeper ex vivo clearance than either agent alone. In venetoclax-resistant xenografts, Val-boroPro suppressed leukemia progression, and adding venetoclax further reduced leukemia burden and prolonged survival beyond either monotherapy. Thus, venetoclax resistance itself exposes an alternative, druggable cell-death program that can be therapeutically exploited to overcome this resistance.

cancer biology↗

bioRxiv2026

Co-targeting KRAS and BCL-2 induces pyroptosis and antitumor tertiary lymphoid structures

Mutant KRAS drives lung tumorigenesis through both cell-intrinsic and cell-extrinsic mechanisms, yet mutation subtype-specific differences in metabolic regulation and immune evasion remain incompletely understood. Here we show that the KRAS G12D mutation, particularly in the KRAS/STK11 co-mutant (KL) context, is associated with poor prognosis and a suppressed immune microenvironment characterized by impaired antigen presentation. At the cell-intrinsic level, G12D exhibits weakened interaction with hexokinase 1 (HK1), reduced spare respiratory capacity, and diminished mitochondrial stress resistance compared with G12C. Based on this mitochondrial vulnerability, we screened a panel of clinically available agents that induce mitochondrial stress and identified that co-targeting KRAS and BCL-2 synergistically triggers GSDME-mediated pyroptosis predominantly in G12D tumors. This combination further induces functional tertiary lymphoid structures (TLS) in vivo. Immune cell depletion experiments further demonstrate that the antitumor efficacy is dramatically dependent on B cells. Moreover, this treatment strategy induced membrane attack complex (MAC) deposition in situ and elicited memory antitumor responses. Collectively, these findings establish that combined KRAS and BCL-2 inhibition elicits pyroptosis and TLS formation, leading to B-cell-dependent in situ and memory antitumor immunity, providing a mechanistic rationale for targeting mitochondrial-immune crosstalk in KRAS G12D-mutant lung cancer.

cancer biology↗

bioRxiv2026

Benchmarked sequencing methods reveal hidden mosaic variation in the human brain

Mosaic variants (MVs) record cellular lineages, but their recovery is strongly method-dependent. Here, we benchmarked four duplex sequencing methods alongside bulk and single-neuron genome sequencing in matched human brain tissue. The methods differed in genome representation, MV yield and mutational profiles, with limited caller-level concordance. However, read-level interrogation revealed substantially greater cross-method molecular support. To systematically recover this evidence, we developed Read-level Integration for Variant Evidence Recovery (RIVER), expanding the pool of cross-method-supported candidates by approximately two orders of magnitude relative to caller-level overlap. Orthogonal sequencing at ~10,000x across brain and peripheral tissues validated approximately half of the tested RIVER-rescued candidates. MVs recovered from a single brain region resolved broadly distributed and regionally restricted clones and provided lineage information among individual neurons. These findings show that RIVER substantially expands the pool of endogenous lineage markers available to investigate human development, aging, disease-associated mosaicism and clonal evolution.

genomics↗

bioRxiv2026

Alignment-Aware Genomic Coordinate Encoding for Long-Range DNA Modeling

Existing genomic foundation models (GFMs) are adept at capturing local, sequential dependencies in DNA. However, their architectures often struggle to efficiently model gene regulation features, such as sparse motifs and distal regulatory elements that operate beyond linear proximity. Moreover, standard positional encodings fail to fully exploit the reference genome coordinate system. Therefore, we present USM-AA, an alignment-aware genomic foundation model that incorporates reference genome coordinates through a non-contiguous positional encoding, Alignment-Aware Rotary Position Embedding, and an alignment embedding module encoding chromosome, strand, and Compact Idiosyncratic Gapped Alignment Report (CIGAR) information. To improve long-range sequence modeling, USM-AA leverages a reverse-complement masked learning strategy. Pretrained on alignment-aware genomic sequences spanning cross-species evolution and human population variation, USM-AA consistently outperforms existing models across multiple downstream tasks, highlighting the importance of alignment-aware representations for genomic sequence modeling.

genomics↗

bioRxiv2026

Niche-dependent epistasis within the cancer genome shapes metastatic fitness

Epistasis, the genetic interaction between loci, directs non-additive genotype-to-phenotype outcomes. Within a multicellular organism, how the tissue niche (E) shapes gene-by-gene epistasis (GxG) and its phenotypic consequences remains poorly studied. Using tumor lung metastasis as an experimental model, we mapped GxGxE through combinatorial CRISPR perturbation coupled with depletion of defined host myeloid populations in mice. The metastatic niche first selects disseminated tumor cells on GxG epistatic fitness, then drives transcriptome convergence regardless of genotype. Removing anatomically distinct myeloid populations reshaped the metastatic epistasis landscape despite identical tumor genotypes. Gene-by-gene-by-environment epistasis therefore operates at the organismal level, with interaction magnitude and sign set by niche cells. Beyond metastasis, our data suggest that the tissue niche conditions how genetic interactions translate into divergent phenotypes.

genetics↗

bioRxiv2026

Successor representation supports structural learning of syllable sequences

Humans efficiently learn the temporal structure of speech, yet the underlying cognitive mechanisms remain unclear. Recent research in visuospatial sequential memory has proposed the successor representation (SR), important in reinforcement learning, which encodes multi-step transitional relationships. To test whether SR also supports the structural learning of rapidly changing speech syllable sequences, we adapted a pyramid-structured sequential learning paradigm using syllable streams presented at a natural speech rate (~ 4 Hz). Participants exhibited robust structural learning, evidenced by asymmetric memory performance modulated by adjacent transitional probabilities. Notably, the SR model captured recognition performance for non-adjacent syllable pairs. Moreover, SR-based learning effects generalized across all syllable sequences, regardless of adjacency. Furthermore, the effectiveness of SR learning was associated with cognitive flexibility and working memory capacity. Together, these findings suggest that humans rely on effortful SR-like mechanisms for the structural learning of syllable sequences, highlighting a modality-general computational principle for sequential learning across various temporal modulation scales.

neuroscience↗