Biology subjects

Zhang, M.

Publications and source records attributed to Zhang, M..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Differential Transcript Usage Reveals Isoform-Level Remodeling of Tumor Biology in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is characterized by transcriptional reprogramming driven by hypoxia signaling, metabolic rewiring, and immune modulation. While gene-level analyses have defined key features of ccRCC biology, they do not capture isoform-level variation arising from alternative splicing. Differential transcript usage (DTU) represents an additional regulatory layer that may influence protein function, pathway activity, and clinical outcomes, yet its role in ccRCC biology and prognosis remains incompletely understood. We assessed differential expression in 127 ccRCC tumors and 33 normal-adjacent tissues from the Dartmouth Cancer Center cohort, with external validation in 94 CPTAC tumors, adjusting for cell-type proportions. DTU was identified using DRIMSeq/stageR, followed by limmavoom modeling with clinical and tumor microenvironment covariates. Transcript-based consensus clustering defined tumor subgroups, and Cox proportional hazards modeling integrated transcript-level features with clinical variables. In tumor versus normal comparisons, 1,170 transcripts exhibited significant differential usage, mapping to canonical ccRCC pathways with distinct patterns across functional and non-functional transcript classes. Consensus clustering based on transcript us-age identified two subgroups with distinct angiogenic profiles and significant survival differences. Cluster-level analysis revealed DTU in genes involved in cytoskeletal organization (ACTB), immune processes (B2M), extracellular matrix organization (FN1, APLP2), and iron metabolism (FTH1) with protein domain alterations, including the loss of actin-associated domains in ACTB and immunoglobulin-like domains in B2M. Prognostic modeling identified twelve transcripts consistently retained across bootstraps, improving risk stratification over clinical variables alone. External validation confirmed overlapping prognostic transcripts, including FGFR1 and NUCB1. Isoform-level features may serve as biomarkers and therapeutic targets in ccRCC. Statement of significanceTranscript-level analysis uncovers potential regulatory pathways in ccRCC missed by gene-level approaches, revealing isoform-specific alterations that define survival sub-groups and offer potential biomarkers and therapeutic targets.

cancer biology↗

bioRxiv2026

Distinct defense strategies against interbacterial antagonism underpin Acinetobacter persistence in polymicrobial environments

Despite intense interbacterial antagonism mediated by mechanisms such as the type VI secretion system (T6SS), pathogenic Acinetobacter frequently persist within highly competitive polymicrobial infections. How these pathogens navigate such hostile environments to achieve co-existence remains poorly understood. Here, we show that pathogenic Acinetobacter employ distinct, multifaceted strategies to resist elimination by both distantly related competitors and closely related kin. T6SS-active strains outcompete heterologous bacteria by deploying a large and diverse repertoire of antibacterial effectors. In contrast, some naturally T6SS-deficient strains resist exogenous T6SS attacks by elaborating a unique, high-density polysaccharide capsule (KL34) that functions as an effective physical shield. Most intriguingly, we uncover a mechanism that prevents lethal competition among kins. A conjugative multidrug-resistant plasmid encoding T6SS repressors is transferred into aggressive strains upon T6SS-mediated attack, leading to suppression of their antibacterial activity. We also found that conjugation is induced by T6SS attack, which effectively suppresses attacking kin and promotes co-infection in vivo. Together, these findings reveal a dynamic and multilayer defense program that enables Acinetobacter to withstand interbacterial warfare while facilitating co-existence. Our study establishes a paradigm in which damage-triggered plasmid transfer enforces targeted suppression, reshaping microbial interactions in polymicrobial communities.

microbiology↗

bioRxiv2026

Receptive-field sizes during remapping and uniform transsaccadic updating across the visual space

Forward receptive-field (RF) remapping, a mechanism for transsaccadic updating of retinal positions and perceptual stability, transiently changes cells eccentricities and thus could also change their RF sizes, yet few studies examined RF sizes during remapping. A related issue is how the mechanism ensures the desired uniform updating across the visual space - a subtraction of the saccade vector from stimulis retinal positions wherever they appear - given highly nonuniform RF sizes and cortical magnification over eccentricities. We analyzed our recent circuit model for remapping/updating after incorporating eccentricity-dependent RF sizes and found that when the corollary-discharge-gated connections achieve uniform updating in the visual space, the model predicts no change to cells RF sizes despite their receiving inputs from other cells with different RF sizes. In contrast, if the updating were uniform in the cortical space but not visual space, cells RF sizes would change during remapping. We analyzed the data from the lateral intraparietal area and frontal eye fields and found that remapping magnitudes are similar for cells of different eccentricities. We then confirmed the prediction that RF sizes did not change significantly during remapping. These results reveal a circuit mechanism for uniform updating and perceptual stability across the entire visual field.

neuroscience↗

bioRxiv2026

Structure and function of human NXPE1, a sialic acid O-acetyltransferase

Human genetic studies have identified defects in multiple mechanisms that predispose the risk of developing inflammatory bowel diseases (IBD), which include alterations in adaptive and innate immune responses, epithelial integrity and regulation of the intestinal mucus layer. Despite the importance of intestinal barrier integrity in the pathogenesis of IBD, essentially all current therapies modulate the immune responses. In this study, we determined the high resolution cryo-EM structure of human NXPE1, a IBD associated protein. Based on the structural homology, we identified NXPE1 as an O-acetyltransferase. Since NXPE1 is a pseudo gene in mouse, we generated knockout mouse model that lacked two of the mouse NXPE1 homologs, Nxpe2 and Nxpe4. The O-acetylation of sialic acid on red blood cells was abolished in the double knockout mice, confirming the sialic acid O-acetyltransferase function of NXPE1 family members. These findings underscore the potential of NXPE1 as a novel therapeutic target of the intestinal barrier functions for the treatment of IBD.

immunology↗

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↗

bioRxiv2026

Cell-type-resolved RNP topologies reveal dynamic structural mechanisms of splicing and therapeutic targets

Resolving RNA conformations in native ribonucleoprotein (RNP) complexes remains a fundamental challenge. Here, we introduce spatial hydroxyl acylation reversible crosslinking with immunoprecipitation (SHARCLIP) to simultaneously capture RNA-RNA, RNA-protein and protein-protein contacts in cells. SHARCLIP profiling of HNRNPC-associated RNA conformations established a global phased map of ribonucleosomes, resolving a decades-old debate on heterogenous nuclear (hn)RNP assembly. We built a dynamic structural atlas across seven cell lineages for >10,000 RNAs, generating ~200 million contacts, and identifying millions of dynamic loops, steric blockers and conformational switches that control splicing outcome. Deciphering the structural logic of mutually exclusive exons (MXEs) enabled rational design of structure-breaking and stabilizing antisense oligonucleotides (ASOs). We demonstrate effective isoform swapping in 12 genes linked to genetic disorders. SHARCLIP provides a comprehensive roadmap for cellular RNA structural biology and structure-guided RNA therapeutics.

molecular biology↗

bioRxiv2026

De novo design of transmembrane accessory subunits for fold stabilization and expansion

Transmembrane (TM) proteins play essential roles in biology as transporters, ion channels, chaperones, enzymes, and mediators of signal transduction. However, membrane proteins often suffer from inefficient folding and intrinsic instability. Misfolding in cells can cause numerous loss-of-function pathologies. Likewise, denaturation upon purification in the laboratory is a critical barrier to structure determination and characterization of key biochemical mechanisms. Generalizable strategies to stabilize membrane proteins remain limited. Here, we developed an informatics-based de novo design strategy to create synthetic auxiliary subunits that interact with the TM helices of a model pentameric ion channel, thereby bolstering folding while maintaining channel function. Biochemical and structural characterization reveal the synthetic TM subunits can also be used to create larger multi-spanning designer proteins of custom topology. This proof-of-concept motivates the feasibility of computationally designed accessory TM helices as potential pharmacological chaperone "folding correctors" of membrane proteins in disease and as tools in structural biology.

biochemistry↗

bioRxiv2026

An fMRI dataset of verbalized spontaneous thought with annotated transcripts and self-report trait measures

Spontaneous thought is pervasive in everyday human cognition, yet datasets capturing its neural dynamics under minimally interrupted conditions remain limited. The current dataset was acquired from a think-aloud functional MRI experiment in which 118 participants continuously verbalized their spontaneous thoughts during 10-minute scanning sessions. The raw MRI data and verbal transcripts with sentence-level timestamps were previously released and analyzed in our prior study examining neural activity associated with thought transitions. Building on that release, we additionally provide preprocessed MRI data, speech transcriptions with word-level timestamps aligned to image acquisition, large language model-generated ratings of transcribed thoughts across emotional and sensory dimensions, and self-report survey measures assessing personality, mental health, and cognitive abilities. Validation analyses demonstrated activation in expected cortical regions associated with speech production and sensory content identified from transcript annotations, agreement between language model and human ratings, and adequate internal consistency of survey measures, supporting the datasets overall quality. This dataset enables reuse for investigations of spontaneous thought, speech generation, and individual differences using naturalistic functional MRI data.

neuroscience↗

bioRxiv2026

Organoid modeling of tumor-associated macrophages reveals phagocytosis checkpoint blockade-induced conversion to an immunosuppressive SPP1+ phenotype

Tumor-associated macrophages (TAM) exert essential functions during the immune response to cancer. However, investigations of TAM within a native human tumor microenvironment (TME) have been impeded by a lack of appropriate model systems. Here, patient-derived organoids (PDO) from air-liquid interface (ALI)-grown tumor fragments, containing a human TME that encompassed stroma and immune subsets, robustly preserved TAM that were maintained by endogenous CSF-1 and appropriately responded to polarization signals. Antibody blockade of the CD47 regulatory checkpoint in organoids stimulated phagocytosis and remodeled TAM cytokine secretion profiles that were confirmed in anti-CD47 phase I trial patients. Amongst PDO histologies screened, anti-CD47 tumor killing was notable in clear cell renal cell carcinoma (ccRCC) which was associated with increased TAM infiltration. PDO contained diverse previously described TAM subsets; however, anti-CD47 reprogrammed organoid TAM toward an immunosuppressive SPP1+ phenotype, highlighting a negative feedback mechanism. Our findings uncover a resistance circuit engaged by macrophage checkpoint blockade and position ALI PDO as a robust translational platform for dissecting human macrophage biology and informing precision immunotherapy.

cancer biology↗

bioRxiv2026

PromptBio-Bench: Benchmarking LLM-based Bioinformatics Agents for End-to-End Data Analysis

Large language model (LLM)-based agents hold transformative potential for automating bioinformatics workflows; however, systematic evaluations of their capabilities remain limited, hindering a clear assessment of their readiness for real-world application. We introduce PromptBio-Bench, a comprehensive evaluation suite of 244 expert-curated tasks spanning bioinformatics and data science at varied difficulty levels, and an evaluation framework for structured file comparison and scoring against expert reference answer files. Evaluation of three state-of-the-art bioinformatics agents revealed comparable performance between Biomni and ToolsGenie, with all agents showing a marked decline in accuracy as task difficulty increased. As foundation models and agent frameworks continue to evolve, PromptBio-Bench provides a valuable benchmark infrastructure for systematically tracking progress in agentic bioinformatics.

bioinformatics↗

bioRxiv2026

Retroelement Hypomethylation Links Hypoxia Signaling, Immune Phenotypes, and Survival in Clear Cell Renal Cell Carcinoma

BackgroundRetrotransposable elements (RE) comprise approximately 45% of the human genome and are typically repressed by DNA methylation to preserve genomic integrity. In cancer, global DNA hypomethylation can lead to RE derepression, resulting in genomic instability and activation of innate immune pathways through viral mimicry. While individual RE classes have been examined in clear cell renal cell carcinoma (ccRCC), the integrated epigenetic landscape of multiple RE families and their clinical relevance remain incompletely characterized. MethodsWe performed a genome-wide prediction of DNA methylation across three major RE classes (Alu, LINE-1, and LTR elements) using a validated computational framework applied to Illumina methylation array data from two independent ccRCC tumor cohorts. Integrated unsupervised clustering of RE methylation profiles was used to define the epigenetic subtypes. Associations with clinicopathologic variables, tumor immune microenvironment composition (DNA Methylation-derived), hypoxia signaling, innate immune activation, and overall survival were evaluated. Prognostic relevance was assessed using multivariable Cox regression models adjusting for age, sex, AJCC stage or AUA risk group, and immune and angiogenic tumor microenvironment features. Key findings were then externally validated in CPTAC-ccRCC and independently replicated in an institutional Dartmouth Cancer Center (DCC) cohort with matched methylation and RNA-sequencing data. ResultsIntegrated clustering identified three reproducible RE methylation subtypes, Repressed, Transient, and Active. In the discovery cohort, the Active subtype showed significantly worse overall survival than the Repressed subtype, with a graded survival pattern across RE methylation states that persisted after multivariable adjustment. RE hypomethylation was associated with reduced EPAS1 (HIF2A) expression, increased immune infiltration, elevated PD-1 expression, and heightened cGAS-STING and interferon signaling, consistent with an immune-inflamed yet immunosuppressed tumor state. In the external CPTAC validation cohort, RE methylation subtypes recapitulated key molecular features and showed supportive survival trends. In the independent DCC replication cohort, an Active RE state was again associated with poorer survival, lower EPAS1 expression, increased PD-1 expression, greater CD8 T-cell and Treg infiltration, and elevated T-cell exhaustion signatures, supporting the reproducibility of the prognostic and immune-exhausted phenotype across cohorts. ConclusionsWe identified RE methylation subtypes with distinct molecular, immunologic, and prognostic features in ccRCC. External validation in CPTAC and independent replication in DCC support the robustness of this RE methylation framework across large-scale and institutional cohorts. These findings highlight the prognostic potential of RE methylation profiles and support their integration into molecular classification strategies to improve risk stratification in ccRCC.

cancer biology↗

bioRxiv2026

Hex-MASP for Mapping the Whole-tissue Spatial Proteome and the Intra-brain Distribution of Monoclonal Antibodies

Whole-tissue spatial proteomics level provides critical insights into region-specific biological regulations but remains challenging. Previously, we introduced the Micro-scaffold Assisted Spatial Proteomics (MASP) concept for whole-tissue mapping. However, this prototype required substantial development in spatial resolution, practicality, and throughput for practical application. Here we present a next-generation MASP technique (hex-MASP) featuring i) a new design of hexagonal-micro-wells fabricated with optimized Projection Micro-Stereolithography (P{micro}SL) 3D-printing, achieving high spatial resolution, sampling robustness and mechanical strength for reproducibly compartmentalizing even tough tissues; ii) enhanced throughput/effectiveness in sample preparation and LC-MS analysis with high quantitative quality. Applied to mouse brain, hex-MASP for the first time achieved in-depth, whole-tissue mapping for >6,000 proteins in mouse brains, with high spatial accuracy and excellent data quality. The substantially improved resolution revealed critical regional details across the entire brain, that were not previously captured, enabling precise depiction of protein distribution heterogeneity. This technique enabled the discovery of many unreported regionally-enriched proteins across brain structures. We further applied hex-MASP to investigate the intra-brain distribution of intracerebroventricularly-dosed antibody therapeutics and related proteins, which to our knowledge, enabled whole tissue mapping of protein drugs for the first time and revealed novel mechanistic insights into antibody distribution and localized treatment effects. Hex-MASP represent a robust, scalable platform for whole-tissue spatial proteomics.

pharmacology and toxicology↗

bioRxiv2026

Attentional prioritization enhances the accessibility of neural representations during working memory maintenance

Given the limited capacity of working memory (WM), prioritization is essential for efficient information processing. Whether prioritization acts primarily at encoding, or dynamically shapes representations during maintenance, is currently unclear. Here, we employed a two-item delayed-match-to-sample task and compared prioritization conditions in which the testing order of items was either known in advance or not. Behaviorally, prioritization selectively reduced guess rates, without affecting precision. Using multivariate pattern analysis, we decoded stimulus information from EEG voltage and indexed internal attention using alpha-band patterns. Prioritization did not alter decodable representations during encoding. During maintenance, however, prioritization enhanced both voltage-based decodability and alpha power-based decodability for the currently prioritized item. Mediation analyses further indicated that alpha-based attentional signals influenced behavior indirectly, via voltage-based representational strength, which is consistent with the idea that internal attention supports performance by strengthening prioritized representations during memory maintenance. Significance StatementWM is capacity-limited, requiring the prioritization of information most relevant to current task demands. Whether prioritization is established at encoding or emerges during maintenance, and how it improves working memory performance, remains unclear. Comparing conditions with and without advance priority knowledge, we found that prioritization occurred primarily during maintenance rather than encoding. We also found that prioritization improved performance by directing internal attention to prioritized items, strengthening their neural representations and increasing their accessibility. This finding provides insight into the flexibility of working memory in the updating of already-encoded information.

neuroscience↗

bioRxiv2026

Axonal swelling as a neuron-specific compartment to sequester and expel misfolded proteins

Neurons are long-lived, highly specialized cells with extended neurites, requiring precise control of misfolded proteins over time and space. Yet, where misfolded proteins are directed and how quality-control pathways adapt during aging are still unresolved. Here, we identify a neuron-specific quality-control compartment that emerges in neurites as aggresome function declines with age, which we call SolAS (Soluble Misfolded Proteins-induced Axonal Swellings). These structures not only sequester misfolded proteins but also facilitate their clearance via microvesicles and exophers. During aging, neurite SolAS and soma aggresomes function hierarchically to maintain proteostasis, with aggresomes acting as the primary sequestration sites in young neurons and SolAS taking over this role as their function declines with age. This transition is driven by a shift from a ubiquitin-dominant to a SUMO-dominant balance. Moreover, solid pathogenic amyloids, such as GA50, can be converted into soluble forms and sequestered into SolAS via SUMO fusion, thereby reducing neurotoxicity. Our findings identify a previously unrecognized neuronal quality-control pathway critical for proteostasis during aging.

neuroscience↗

bioRxiv2026

Coordinated phase separation and phase transition underlie synaptic ribbon condensate formation and plasticity

Mesoscale molecular apparatuses with diverse functions are widespread in cells. How mesoscale cellular apparatuses are formed and regulated is poorly understood. The synaptic ribbon in sensory neurons, which can dynamically adjust its size and shape in response to light or sound, is a mesoscale molecular assembly. In this study, we demonstrate that RIBEYE, the backbone protein of synaptic ribbons, via combined ordered and disordered interactions, forms micron-sized dynamic molecular assemblies. Integrated cryo-electron microscopy and tomography studies revealed that the N-terminal SAM domain and the C-terminal B domain of RIBEYE form distinct nanoscale filaments and further assemble into ribbon-like architectures via phase transition. Unexpectedly, the N-terminal intrinsically disordered region of RIBEYE softens the solid mesoscale ribbon structures via phase separation. The mesoscale size and shape of the RIBEYE condensate are bidirectionally tuned by physiological modulators such as Piccolino and CtBP1, linking synaptic ribbon structural plasticity to functional adaptability. Thus, our study demonstrates that combined phase transition and phase separation of nanoscale protein oligomers can build mesoscale functional cellular apparatuses.

biochemistry↗

bioRxiv2026

RIPK3 suppresses photoreceptor degeneration in a Stargardt disease mouse model

Autosomal recessive Stargardt disease type 1 (STGD1) is the most prevalent inherited juvenile macular degeneration, ultimately leading to irreversible blindness through photoreceptor cell loss, yet the underlying cell death mechanisms remain poorly defined. Receptor-interacting protein kinase 3 (RIPK3) is a well-established mediator of necroptosis and, under certain circumstances, apoptosis downstream of TNF family ligands, and it was found to be progressively upregulated in the retina of a STGD1 abca4-/-rdh8-/- (DKO) mouse model coinciding with the onset and progression of photoreceptor degeneration. Despite elevated RIPK3 expression, necroptosis was not detectable in this model, as evidenced by the absence of phosphorylated MLKL and unaltered photoreceptor degeneration in abca4-/- rdh8-/-mlkl-/- mice. Intriguingly, genetic ablation of Ripk3 exacerbated photoreceptor loss in DKO mice in both chronic (age-dependent) and acute (light-induced) retinal degeneration paradigms. This detrimental effect was partially ameliorated by pan-caspase inhibition in the acute degeneration model, indicating caspase-dependent apoptosis as the primary executioner. Mechanistically, we demonstrated that RIPK3 suppressed extrinsic apoptosis by attenuating caspase-8 activation downstream of TNF family ligands. Collectively, our findings reveal a non-canonical, protective role of RIPK3 in photoreceptors, as a brake on apoptotic signaling rather than a necroptotic executor, in the context of STGD1. These findings redefine the role of RIPK3 in retinal degeneration and emphasize the contextual plasticity of cell death regulators in neurodegenerative diseases.

neuroscience↗

bioRxiv2026

Coenzyme A is a redox sensing cofactor for malic enzyme 2 regulating oxidative stress and mitochondrial metabolism

Coenzyme A (CoA) is an essential cofactor required for numerous metabolic reactions, yet its ability to bind and regulate proteins remains poorly defined. Using a proteomic approach, we identified malic enzyme 2 (ME2) as a CoA-binding protein. ME2 uses NAD(P)+ to convert malate to pyruvate, generating NAD(P)H to support energy production and redox homeostasis. ME2 binds CoA at an allosteric site previously thought to bind NAD(P)+. Reduced CoA has minimal effect on ME2 activity, but the oxidized form, CoA disulfide, strongly activates ME2 by promoting ME2 tetramerization and a catalytically efficient closed conformation. Under oxidative stress, ME2 facilitates CoA disulfide formation, enhancing NADPH production and cellular defense against reactive oxygen species (ROS). Mice with ME2 mutation that cannot bind CoA show impaired muscle performance, elevated ROS, and mitochondrial dysfunction. These findings establish CoA as a redox-sensing cofactor, allowing cells to respond to ROS and promote mitochondrial metabolism, and expanding the function of this essential cofactor.

biochemistry↗

bioRxiv2026

Synovial transcriptional clusters link cartilage degeneration to cell-type-specific gene expression in knee osteoarthritis

ObjectivesTo identify synovial transcriptional clusters in human knee osteoarthritis (OA) and determine how these relate to synovial histologic features, cell-type-associated gene expression, and cartilage degeneration severity. MethodsBulk RNA sequencing (RNA-seq) of synovial tissue from n = 135 patients with knee OA was analyzed using consensus clustering. Clusters were compared by clinical and histologic features, including cartilage degeneration severity (OARSI score). Single-cell RNA-seq (n = 18) and spatial transcriptomics were used to relate cartilage degeneration-associated gene expression patterns to synovial cell populations. ResultsFour synovial transcriptional clusters that differed in synovial histologic features and cartilage degeneration severity were identified. Greater cartilage degeneration was associated with enrichment of lining fibroblast- and inflammatory myeloid-associated gene expression, whereas lesser cartilage degeneration was associated with enrichment of sublining fibroblast, endothelial, mural cell, and adipocyte-associated gene expression. ConclusionsHuman knee OA synovium segregates into transcriptional clusters associated with cartilage degeneration severity. Synovial transcriptional heterogeneity corresponds to cell-type-associated gene expression. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIOsteoarthritis synovium exhibits marked histologic and molecular heterogeneity. C_LIO_LISynovial inflammation detected by MRI correlates with cartilage degeneration and predicts progressive cartilage loss in knee OA. C_LIO_LIPrior transcriptomic studies have identified molecular subsets of OA synovium, but their relationship to cartilage degeneration severity remains unclear. C_LI What this study addsO_LIOA synovium segregates into four transcriptional clusters: Sublining (C1), Lymphomyeloid (C2), Myeloid (C3), and Major trauma (C4). C_LIO_LIGreater cartilage degeneration is associated with enrichment of inflammatory myeloid and lining fibroblast gene expression, whereas lesser degeneration is associated with enrichment of adipocyte, sublining fibroblast, endothelial, and mural cell-associated gene expression. C_LI How this study might affect research, practice or policyO_LIProvides a framework for a clinically relevant biological stratification of OA patients based on synovial molecular features. C_LIO_LIInforms future efforts to link synovial biology with OA prognosis, cartilage degeneration, treatment allocation, and development of targeted therapeutic strategies. C_LI

genomics↗