Biology subjects

Qi, Z.

Publications and source records attributed to Qi, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Long-range transport of biomolecular condensates by Marangoni effect

How mesoscale cargos such as biomolecular condensates are transported and spatially positioned within cells remains a fundamental question in cell biology. During Caenorhabditis elegans zygote polarization, a substantial fraction of P granules undergoes persistent anterior-to-posterior motion that cannot be fully explained by dissolution-recondensation. Here, combining microfluidic reconstitution, quantitative micropipette aspiration and live-cell imaging, we show that a MEG-3 concentration gradient generates interfacial-tension asymmetry and drives the directed transport of PGL-3-RNA co-condensates in vitro and P granules in vivo through the Marangoni effect. This framework enables parameter-free quantitative predictions of condensate transport. Orthogonal molecular perturbations abolish or reverse directional migration, directly linking interfacial properties to transport behavior and establishing the specificity of this mechanism. Together, our findings identify the Marangoni effect as a previously unrecognized mechanism for intracellular transport of biomolecular condensates and provide direct causal evidence that condensate emergent properties can contribute to physiological organization.

biophysics↗

bioRxiv2026

Therapeutic Potential of iPSC-Derived TH+FOXA2+ Neuronal Extracellular Vesicles in Parkinson's Disease Revealed by Organoid and Rodent Models

Background: Parkinson's disease (PD) is characterized by the progressive loss of midbrain dopaminergic (DA) neurons and aberrant alpha-synuclein (alpha-syn) aggregation, yet disease-modifying therapies that simultaneously retard neurodegeneration and foster regeneration remain lacking. Methods: In this study, we isolated extracellular vesicles (TH and FOXA2 double-positive cell-derived EVs) from TH and FOXA2 double-positive differentiated neural cells, a distinct midbrain floor-plate-derived neural cell population that co-expresses the floor-plate transcription factor FOXA2 together with TH and should therefore not be equated with conventional mature midbrain dopaminergic neurons, and systematically evaluated their therapeutic potential across three complementary models: A53T transgenic mice, 6-OHDA-lesioned rats, and 6-OHDA-treated human midbrain organoids. Integrative transcriptomic and single-cell sequencing analyses, together with toxicological evaluations in rodents and non-human primates, were performed to investigate the underlying mechanisms and safety profile. These TH and FOXA2 double-positive cells were generated using a fully suspension-based, matrix-free, and chemically defined differentiation system devoid of N2/B27 supplements and fetal bovine serum (FBS). This approach offers a simple, controllable, low-cost, and scalable platform with high batch-to-batch consistency for EV manufacturing. Throughout this study, the term "TH and FOXA2 double-positive cells" refers to this distinct TH and FOXA2 double-positive cell population and should not be interpreted as conventional terminally differentiated dopaminergic neurons. Results: Intranasal administration of TH and FOXA2 double-positive cell-derived EVs in A53T mice and 6-OHDA-lesioned rats significantly ameliorated motor deficits, increased nigral tyrosine hydroxylase (TH)-positive neuron counts, reduced alpha-syn aggregation, and suppressed gliosis. In human midbrain organoids, TH and FOXA2 double-positive cell-derived EVs preserved DA neuronal morphology and reduced GFAP and alpha-syn expression. Notably, when EVs were administered simultaneously with 6-OHDA modeling rather than after modeling was completed, the protective effect was stronger. Multi-omics analysis revealed that TH and FOXA2 double-positive cell-derived EVs reversed pathological signatures of interferon-responsive microglia and oxidative stress-adapted astrocytes, while restoring WNT- and non-canonical WNT-mediated intercellular communications. Safety evaluations showed no discernible organ toxicity. Conclusions: TH and FOXA2 double-positive cell-derived EVs exert neuroprotective effects across multiple PD models by modulating specific glial subpopulations and reinstating development-associated signaling pathways. Together with a fully suspension-based, matrix-free, and N2/B27-free differentiation process that enables low-cost, scalable, and highly reproducible manufacturing, TH and FOXA2 double-positive cell-derived EVs represent a promising therapeutic candidate for Parkinson's disease.

neuroscience↗

bioRxiv2026

A Medicinal Chemistry-Centered Evaluation of AlphaFold 3 and Boltz-2 Across Diverse Binding Modalities

AlphaFold 3 (AF3) and Boltz-2 are state-of-the-art AI-based tools for biomolecular structure prediction, but whether their predictions provide useful guidance for lead optimization, SAR interpretation, and virtual screening remains insufficiently characterized. We benchmarked their performance using newly determined soluble epoxide hydrolase co-crystal structures and matched activity data together with a curated post-training-cutoff dataset spanning kinases, allosteric modulators, covalent systems, PROTACs, molecular glues, fragments, membrane proteins, RNA binders, and activity-cliff pairs. Both models recovered canonical orthosteric enzyme and kinase complexes, including key DFG/C conformational states, whereas allosteric, membrane-protein, and induced-proximity complexes remained challenging. Pharmacophore RMSD was often lower than overall ligand RMSD, indicating preservation of key recognition features despite imperfect whole-ligand alignment. AF3 minPAE correlated with pose accuracy, and very low minPAE values (<0.85 A) were strongly enriched for accurate poses. Model confidence scores were not associated with experimental activity, whereas Boltz-2 predicted affinity captured relative activity trends and distinguished the activity-cliff pair, although its performance varied across ligand series.

biochemistry↗

bioRxiv2026

A Centimeter-Scale, Peristaltic Human Intestinal Organoid with Integrated Neuro-Immune-Vascular Systems Recapitulates Enteritis and Orthotopic Colorectal Cancer

Human pluripotent stem cell-derived intestinal organoids hold great promise for disease modeling, drug screening, and regenerative medicine. However, conventional intestinal organoids are predominantly epithelial, small in scale, and lack the multicellular complexity required to recapitulate the pathophysiology of intestinal disorders such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). Here, we report the development of Centimeter-Scale, purely 3D self-organized human intestinal organoids (IOs) from induced pluripotent stem cells (iPSCs) that encompass multiple tissue lineages, including epithelium, mesenchyme, smooth muscle, neurons, immune cells, and vasculature. These organoids achieve functional maturation by day 100+, exhibiting rhythmic peristaltic-like contractions, and by day 147 they display histological structures including lumens, crypt-like architecture, goblet cells, and smooth muscle. Importantly, for the first time, the neuro-muscle lineages arise spontaneously and autonomously in a purely 3D culture system, without any external stimulation (e.g., electrical, chemical, or mechanical), and mature to form functional neuromuscular junctions, driving macroscopically visible peristaltic-like contractions that mimic intestinal motility entirely through in vitro culture, without any xenotransplantation. Single-cell RNA sequencing at day 115 identified 12 cell subtypes across four major lineages, recapitulating the cellular diversity of the developing human intestine. Using this platform, we established an LPS/IFN-{gamma}-induced IBD model that recapitulated key pathological features, including epithelial disruption, immune cell infiltration, and IL-6 elevation. Transcriptomic analysis confirmed activation of the NF-{kappa}B and JAK2-STAT3 pathways, multi-modal cell death, and immune recruitment machinery, all consistent with clinical IBD pathology. Furthermore, we developed intestinal cancer models at 7 and 21 days showing abnormal hyperplasia, and a probiotic co-culture system demonstrating anti-inflammatory efficacy. Together, these results establish Centimeter-Scale intestinal organoids as a physiologically relevant, multicellular platform for modeling intestinal diseases and evaluating therapeutic interventions.

cell biology↗

bioRxiv2026

BCL11B predetermines a persister state in breast cancer that is reversed by TNFα

The frequent development of chemoresistance in cancer presents a significant clinical challenge, yet the underlying causes for heterogeneous drug responses remain largely elusive. Here, we systematically assessed the cellular differentiation status of human breast cancer cells utilizing single-cell atlases and identified a distinct population of immature basal-like cancer cells marked by BCL11B. Notably, higher levels of BCL11B+ cancer cells are significantly associated with early relapse in breast cancer patients who received chemotherapy. Functioning as a central regulator, BCL11B delineates an immature cell state that preferentially transitions to a drug-resistant persister state during treatment through multiple pre-existing and adaptive drug-resistance programs. Importantly, the cytokine tumor necrosis factor alpha (TNF) is revealed as a natural inhibitor of BCL11B and can directly reverse the emergence of chemoresistant persister cells. Therefore, we identify BCL11B as an unappreciated pre-determinant of drug response and a therapeutic target for a subset of breast cancer patients at high risk of developing chemoresistance.

Cancer Biology↗

bioRxiv2026

Chaperonin recognition of protein dynamics drives drug resistance

The emergence of drug resistance is typically driven by mutations that alter drug-target affinity, yet the role of host cellular machinery regulating these processes remains unclear. Here, we reveal that the chaperonin GroEL/S promotes drug resistance through recognition of protein dynamics. Using directed evolution of E. coli DHFR under antibiotic stress and varying GroEL/S expression, we identify a well-folded resistance variant whose fitness, despite tight inhibitor binding, is critically potentiated by GroEL/S engagement. X-ray crystallography, NMR, molecular dynamics and kinetic modeling reveal that millisecond-timescale flipping of the M20 loop generates steric accessibility and a kinetic window for chaperonin interaction that forcibly displaces tightly bound inhibitors, thereby overriding thermodynamic equilibrium of inhibitor binding to restore the active enzyme pool and preserve metabolic flux. Our findings not only reveal a novel paradigm of "dynamic recognition" where both conformational kinetics and distribution govern chaperonin recognition but also establish chaperonins as "deligandases" that actively modulate in vivo drug binding, suggesting that chaperone surveillance of the cellular proteome extends beyond quality control to govern native protein function. This mechanism defines a previously unrecognized route for the rapid development of drug resistance, with implications for understanding therapeutics of microbial infections and human malignancies.

biophysics↗

bioRxiv2026

Integrating Histology with Spatial Molecular Programs Using a Multimodal Foundation Model

Histopathological assessment remains central to cancer diagnosis and stratification, yet its mechanistic interpretation remains limited without molecular context. To address this, we developed SQUALL, a multimodal foundation model integrating histology with spatial molecular programs. For pretraining, we assembled histMol, a large-scale corpus of 1.76 billion paired histology-spatial transcriptomics spots/bins across 33 tissues and 12 platforms from 3,446 tissue sections. Following pretraining, SQUALL enables transcriptome-wide virtual biomarker profiling, prognostically relevant spatial niches discovery, and integrative disease progression modeling. Leveraging its multimodal embeddings, SQUALL identifies niches associated with tertiary lymphoid structure (TLS) maturation and ovarian cancer relapse, reconstructs molecular trajectories of breast cancer invasion across 325,112 spots, and uncovers underlying transcriptional programs. Applied to whole-slide images from 898 patients, SQUALL outperforms existing pathology foundation models in outcome prediction while enabling interpretable risk stratification. Together, these results establish spatially aligned multimodal pretraining as a new paradigm for extending molecular insights into pathology images.

bioinformatics↗

bioRxiv2026

Molecular grammar of RNA m6A modification in ribonucleoprotein granules

Diverse RNA chemical modifications collectively regulate nearly all aspects of RNA metabolism. Among these, N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic messenger RNAs. Recent studies have implicated m6A in the formation and regulation of ribonucleoprotein (RNP) granules--biomolecular condensates that organize RNA metabolism in space and time. However, the underlying biophysical mechanisms remain to be elucidated. Here, building on SMART, a single-molecule platform for quantitatively measuring RNP granule assembly across nanometer-to-mesoscale regimes, we develop SMART-epi to enable precise control of the m6A modification ratio. Using this approach, we show that physiological m6A levels inhibit YTHDF2 RNP granule assembly while directing specific RNA-RNA interaction architectures. Moreover, YTHDF1/2/3 exhibit distinct assembly kinetics, suggesting functional divergence. Together, these findings reveal a molecular grammar by which m6A modulates condensate dynamics and suggest that RNA modifications can encode regulatory information to tune RNP granule behavior, with potential implications for therapeutic intervention.

biophysics↗

bioRxiv2026

Development of a Fully Non-Viral 1XX-enhanced BCMA CAR-T Cell Therapy for Multiple Myeloma

Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by bone marrow infiltration, monoclonal immunoglobulin production, and microenvironmental dysregulation that leads to systemic organ damage. The advent of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has induced unprecedented responses and durability for patients with relapsed/refractory MM. These outcomes are rarely observed with prior salvage strategies, although relapse remains the predominant long-term challenge for most patients. The two currently approved BCMA CAR-T cell products use viral vectors to semi-randomly insert the CAR gene, which results in heterogeneous genomic composition and variability in efficacy, safety, and product consistency. To address these challenges, we integrated targeted CRISPR genome engineering with precise CAR transgene insertion at the T-cell receptor alpha constant (TRAC) locus, 1XX CAR signaling architecture to enhance potency and durability, and non-viral manufacturing with a single-stranded DNA repair template to improve efficiency and yield. This approach confers physiological CAR expression, reduces insertional mutagenesis, and improves persistence by mitigating tonic signaling and exhaustion. Our GMP manufacturing process consistently achieved high CAR integration (37.7-72.7%) and yields across all full-scale runs and met predefined release criteria for identity, purity, safety, and quality. In NSG mouse models of MM, the UCCT-BCMA-1 product exhibited exceptionally potent tumor control, CAR-T cell expansion 100-1000-fold greater than that of lentiviral constructs, and durable clearance of myeloma cells after multiple rechallenges. These findings establish a CRISPR-edited, fully non-viral manufacturing platform for next-generation 1XX-BCMA CAR-T therapies with enhanced persistence, safety, and efficacy. One Sentence SummaryCRISPR-engineered, TRAC-targeted 1XX-BCMA CAR-T therapy with improved safety, potency, and persistence in relapsed and refractory multiple myeloma.

cancer biology↗

bioRxiv2026

Midazolam suppresses glioma progression by attenuating neuronal activity and downregulating IGF1 signaling

Glioma is the most common primary malignant tumor of the brain, and accumulating evidence indicates that neuronal activity plays a pivotal role in tumor progression. In this study, neuronal activity is modulated in vitro using potassium chloride (KCl)-induced depolarization and midazolam (MDZ)-mediated suppression. MDZ is a neuronal activity modulation medication, commonly used for sedation, anxiolysis, and amnesia in clinics. After treatment, conditioned media derived from these neuronal cultures are subsequently co-cultured with glioma cells. EdU incorporation assays demonstrate that MDZ significantly inhibits glioma cell proliferation in vitro. Furthermore, an orthotopic xenograft glioma model is established to assess the anti-tumor efficacy of MDZ in vivo, as evaluated by tumor volume and Ki-67 immunostaining. Mechanistically, insulin-like growth factor 1 (IGF1) is identified as the neuronal-activity-regulated factor that promotes glioma growth through activation of the PI3K/AKT signaling pathway. Moreover, transcriptomic profiling of brain tissues reveals that MDZ attenuates neuronal activity and downregulates neuron-derived growth factors in both glioma and non-tumor regions, thereby exerting anti-tumor effects in vivo. Collectively, these findings demonstrate that MDZ suppresses glioma progression by suppressing neuronal activity and inhibiting neuron-derived trophic factors, providing new insights into the development of therapeutic strategies for glioma.

neuroscience↗

bioRxiv2026

Immediate transcriptional changes initiated by direct cell-cell contact between cytotoxic T cells and cancer cells

Many biological processes are regulated by the direct interaction between two or more cell types. However, our understanding of the immediate dynamic changes in gene transcription upon physical interaction between two cells has remained limited due to technical limitations. Here we address these limitations in a model system of cancer-specific T cell receptor (TCR)-modified CD8 T cells where single and cancer-interacting T cells were isolated by image-enabled cell sorting and transcripts from heterotypic cancer cell and T cell pairs were in silico assigned. This approach uncovers immediate, dynamic changes in gene expression following the specific interaction between TCR-modified CD8 T cells and cancer cells. In addition to dissecting transcriptional cascades dependent on the peptide sensitivity of the TCR, we for the first time directly compare these gene expression changes between single T cells and T cells in direct physical contact with cancer cells. Modeling of the observed transcriptomic activation signature identifies phenotypically distinct tumor infiltrating CD8 T cell subsets associated with reduced TCR diversity in in vivo datasets. Taken together, the paradigm developed here allows for future clonal identification of T cell receptors mediating ongoing effective cytotoxic responses in vivo.

immunology↗

bioRxiv2026

The kinetics of ribonucleoprotein granules

Ribonucleoprotein (RNP) granules are biomolecular condensates composed of diverse RNAs and RNA-binding proteins that play essential roles in regulating multiple aspects of RNA biology. As complex biological systems, the condensate functions of RNP granules emerge from the higher-order kinetic assembly of individual molecules. Here, we develop an in vitro single-molecule approach--termed SMART (group single-molecule assay for ribonucleoprotein granules)--that enables direct and quantitative measurements of RNP granule assembly and disassembly kinetics across nanoscale to mesoscale regimes. Using SMART, we reveal that RNP granule assembly is strongly pathway dependent. In parallel, we develop a minimal two-state mathematical model that faithfully reproduces these kinetic behaviors. This model enables quantification of multivalent interaction timescales, reconstruction of the underlying free-energy landscape governing RNP granule dynamics, and demonstrates that this assembly process is intrinsically non-equilibrium. Understanding the condensate functions of RNP granules suggests new strategies for their rational manipulation in health and disease.

biophysics↗

bioRxiv2026

NORAD orchestrates KLC1-mediated SFPQ transport via liquid-liquid phase separation

Neuronal function requires precise long-distance axonal transport mediated by molecular motors and RNA-binding proteins like SFPQ, though regulatory mechanisms remain poorly defined. We identify long non-coding RNA NORAD as a master regulator of this process through liquid-liquid phase separation (LLPS). While SFPQ and kinesin-1 mediate cargo delivery, the specific RNA coordinating their interaction was unknown. We demonstrate NORAD directly binds kinesin light chain 1 (KLC1) and promotes SFPQ condensation into dynamic LLPS droplets, enabling efficient transport. CRISPR-assisted mapping and functional assays show NORAD depletion disrupts granule dynamics, impairs neuroprotective mRNA localization, and induces axonal degeneration. In vitro reconstitution confirms NORAD-KLC1 synergy enhances SFPQ phase separation, and neuron-specific knockout mice exhibit motor deficits with reduced neuronal density. These findings establish the first evidence of lncRNA NORAD-mediated LLPS in axonal transport, revealing a new paradigm for RNA-guided neuronal maintenance.

molecular biology↗

bioRxiv2025

Mechanism of single-strand annealing from native mass spectrometry and cryo-EM structures of RAD52 homolog Mgm101

RAD52, the primary single-strand annealing (SSA) protein in humans, forms undecameric rings that bind ssDNA within a narrow, positively-charged groove. Whether RAD52 anneals two complementary ssDNAs on the same ring in cis, or between two ring-ssDNA complexes in trans, is unknown. Here, we determined cryo-EM structures of Mgm101, a RAD52 homolog from yeast mitochondria, in complexes with ssDNA, a duplex intermediate of annealing, and B-form dsDNA product. In all states, Mgm101 forms a closed nonadecameric ring that binds the backbone of the first ssDNA at the base of the narrow groove. The second complementary strand binds directly on top of the first to form an extended, unwound, and circular duplex intermediate of annealing. The third complex captures apparent B-form DNA product bound to a novel {beta}-hairpin motif located on top of the Mgm101 ring, above the primary DNA-binding groove. Mass photometry and native mass spectrometry confirm and further elucidate the complexes formed in solution. Altogether, our data reveal the full SSA pathway of Mgm101 and suggest it anneals two complementary ssDNAs on the same ring in cis. Structural conservation with RAD52 suggests it is likely to use a similar cis mechanism of annealing.

biochemistry↗

bioRxiv2025

Unveiling the Chain Mediation Model of Sleep Quality and Fatigue in Linking Subjective Exercise Experience to Depression in Adolescent

While the positive correlation between physical exercise and depression has been widely replicated in cross-sectional research, the prognostic value of subjective exercise experience for depression continues to be disputed, and the mediating processes are not well understood. This study aims to elucidate the predictive role of subjective exercise experience in depression and examine the chain mediating effects of sleep quality and fatigue. We administered validated self-report questionnaires to assess these constructs in a sample of 538 Chinese high school students. The results demonstrated that adolescents depressive symptoms are influenced by subjective exercise experience, and this effect mediated through two independent pathways: sleep quality and fatigue. Moreover, subjective exercise experience can predict adolescent depression via either the sleep quality pathway or the fatigue pathway. The identification of mediating dual pathways provides empirical support for developing targeted exercise interventions that specifically address sleep disturbances and fatigue management in depressed adolescents.

physiology↗

bioRxiv2025

Hollow condensates emerge from gelation-induced spinodal decomposition

Recent studies have identified diverse hollow biomolecular condensates, characterized by biomolecule-depleted interiors surrounded by biomolecule-rich shells. Although several formation mechanisms have been proposed, a general thermodynamic driving force remains elusive. Here, we investigate a well-defined system in which the human transcription factor p53 and non-specific double-stranded DNA (dsDNA) form biomolecule-rich condensates. Introduction of dsDNA containing p53-binding motifs induces a morphological transition to hollow structures, accompanied by a material state transition from liquid-like to gel-like. In vitro assays indicate that the formation of hollow condensates is driven by p21 DNA-induced localized gelation at the condensate periphery. Guided by these findings, we developed a three-component phase-field model that quantitatively recapitulates the formation of hollow condensates. Simulations show that peripheral gelation leads to gradual depletion of protein and Random DNA from the condensate core, triggering spinodal decomposition and lumen formation inside condensates. Together, these results offer mechanistic insights into multi-component hollow condensates.

biophysics↗

bioRxiv2025

RIP2 inhibits DOCK8-mediated platelet dense granule release and alleviates experimental myocardial infarction

ObjectiveReceptor-interacting protein 2 (RIP2) is an essential mediator of inflammation and innate immunity downstream of pattern recognition receptors (PRRs). Platelets express RIP2, while its role in platelet activation, thrombosis, and myocardial infarction (MI) is unknown. Approach and ResultsHere we show that RIP2 deficiency enhances platelet dense granule secretion in response to GPIb and GPVI activation; platelet aggregation in whole blood and adhesion under arterial shear are also increased. Consistently, RIP2 inhibitor WEHI-345 potentiates human platelet dense granule secretion and inhibits RIP2 phosphorylation induced by thrombin and collagen. These phenotypes are translated into shorter bleeding time, accelerated FeCl3-induced arterial thrombosis. Importantly, platelets from patients with coronary artery disease and mice with atherosclerosis express lower RIP2, and RIP2 deficiency deteriorates MI and cardiac function in a mouse ischemia/reperfusion model. Mechanistically, we found that platelets express dedicator of cytogenesis protein 8 (DOCK8), which is sequestered by phosphorylated RIP2 (p-RIP2), causing inhibition of Cdc42 activation and subsequent dense granule release. ConclusionsIn conclusion, RIP2 inhibits platelet activation, thrombosis, and ameliorates MI. Our results also suggest that a novel PRR-independent pathway, p-RIP2-DOCK8-Cdc42, negatively regulates platelet activation downstream of GPIb and GPVI. Platelet RIP2 pathway may be promising for therapeutic intervention of atherothrombotic diseases from early atherosclerosis stage to arterial thrombosis and MI. HighlightsO_LIRIP2 inhibits platelet dense granule release NOD2-independenly via pRIP2-DOCK8-Cdc42. C_LIO_LIThe negative regulation of RIP2 on platelet activation is translated into enhanced thrombosis, exacerbated myocardial infarction (MI). C_LIO_LIRIP2 pathway booster may be an approach for therapeutic intervention of atherothrombotic diseases. C_LI

molecular biology↗

bioRxiv2025

Mechanistic basis for protection against fatty liver disease by CIDEB loss-of-function mutations

Background & AimsSomatic and germline CIDEB mutations are associated with protection from chronic liver diseases. The mechanistic basis and whether CIDEB suppression would be an effective therapy against fatty liver disease remain unclear. Methods21 CIDEB somatic mutations were introduced into cells to assess functionality. In vivo screening was used to trace Cideb mutant clones in mice fed normal chow, western (WD), and choline-deficient, L-amino acid-defined, high-fat (CDA-HFD) diets. Constitutive and conditional Cideb knockout mice were generated to study Cideb in liver disease. Isotope tracing was used to evaluate fatty acid oxidation and de novo lipogenesis. Transcriptomics, lipidomics, and metabolic analyses were utilized to explore molecular mechanisms. Double knockout models (Cideb/Atgl and Cideb/Ppara) tested mechanisms underlying Cideb loss. ResultsMost CIDEB mutations showed that they impair function, and lineage-tracing showed that loss-of-function clones were positively selected with some, but not all fatty liver inducing diets. Cideb KO mice were protected from WD, CDA-HFD, and alcohol diets, but had the greatest impact on CDA-HFD induced liver disease. Hepatocyte-specific Cideb deletion could ameliorate disease after MASLD establishment, modeling the impact of therapeutic siRNAs. Cideb loss protected livers via increased {beta}-oxidation, specifically through ATGL and PPARa activation. ConclusionsCideb deletion is more protective in some types of fatty liver disease. {beta}-oxidation is an important component of the Cideb protective mechanism. CIDEB inhibition represents a promising approach, and somatic mutations in CIDEB might predict the patient populations that might benefit the most.

physiology↗