Biology subjects

Li, Q.

Publications and source records attributed to Li, Q..

At least 109 records · Page 6Linked to original sources

bioRxiv2026

Distinct contribution of autoreactive B cell Bruton's tyrosine kinase signaling to neuroinflammation

In multiple sclerosis (MS), autoreactive B cells play a central role in driving CD4 T cell-mediated inflammatory damage to myelin (1). Here we investigated how disrupting Brutons tyrosine kinase (BTK) signaling exclusively in B cells shapes the course of experimental autoimmune encephalomyelitis (EAE), a model for MS, through alterations in B cell development and activity. B cell-specific BTK deletion significantly ameliorated both human MOG (hMOG) induced EAE (p = 0.0087) as well as spontaneous disease in 2D2+IgHMOG mice (p = 0.0004). Additionally, MOG-specific cells were found to be more sensitive to loss of BTK than tolerant clones (p = 0.0002) and production of anti-MOG immunoglobulins was also found to be diminished (p < 0.004) while overall IgG was unchanged (p = 0.44). B cells isolated from conditional knockout mice did not upregulate expression of co-stimulatory receptors or MHC II to the same extent as controls when cultured alongside MOG-specific CD4 T cells (p < 0.005) and were inferior at driving T cell proliferation (p < 0.0001) in vitro. Lastly, while BTK deletion diminished the proliferative and survival response of B cells following mitogen stimulation, B cell trafficking to the leptomeninges and organization into ectopic lymphoid tissues (ELTs) in 2D2+IgHMOG mice continued unabated. We identified that BTK signaling regulates several features adopted by autoreactive B cells that contribute to EAE pathogenesis. This study provides mechanistic insights into the therapeutic benefits of BTK inhibitors observed in clinical trials exploring BTK as a therapeutic target in the context of MS. Significance statementAutoreactive B cells contribute to the neuroinflammation that drives multiple sclerosis (MS) and related diseases, yet the molecular mechanisms enabling their pathogenicity remain incompletely understood. This study demonstrates that B cell-specific deletion of Brutons tyrosine kinase (BTK) markedly reduces disease severity in two complementary versions of experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS. Loss of BTK impairs autoreactive B cell survival, antibody production, antigen presentation to encephalitogenic T cells, and T cell activation, while leaving meningeal ectopic lymphoid tissue formation intact. These findings provide direct mechanistic evidence that BTK signaling in B cells promotes neuroinflammatory damage and supports the therapeutic targeting of BTK to limit B cell-driven pathology in MS.

immunology↗

bioRxiv2026

Dynamic dissociation of the IFT complex drives ciliary dysfunction during C. elegans ageing

Intraflagellar transport (IFT) is essential for cilia, and its dysfunction drives ciliopathies and systemic ageing. However, the in vivo dynamics of individual components in the IFT complexes remain obscured, leaving the mechanisms of age-dependent IFT failure largely unknown. Here, we report a dual-color super-resolution imaging strategy to dissect the structural integrity and kinetics of IFT trains in the sensory cilia of young and aged Caenorhabditis elegans. We show that IFT complexes are not static entities. Instead, distinct components undergo dynamic dissociation within IFT trains. This intra-complex dissociation causes a remarkable reduction in IFT velocity and is significantly exacerbated in the cilia of aged worms. Mechanistically, we identify the conserved TRiC/CCT chaperonin complex and daf-19/RFX, the master transcription factor driving IFT genes, as critical regulators of IFT stability. We demonstrate that their age-dependent downregulation drives the progressive IFT component dissociation. Our findings re-frame the IFT complex as a highly dynamic assembly, uncover a new dimension of IFT regulation, and identify the progressive uncoupling of IFT components as a key driver of ciliary dysfunction during ageing.

cell biology↗

bioRxiv2026

Enteroviral epitope mimicry enables NK cell-mediated targeting of ASPH in hepatocellular carcinoma

Cancer development is shaped by host-microbe interactions, including viral infections. While several viruses are established oncogenic drivers, their potential protective roles in cancer remain unclear. Here we identify a dominant antibody response to CE1, a consensus epitope of enterovirus and rhinovirus, that is associated with reduced hepatocellular carcinoma (HCC) incidence and mortality. Anti-CE1 antibodies selectively recognize HCC cells and mediate anti-tumor activity through NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Mechanistically, anti-CE1 antibodies cross-react with aspartate {beta}-hydroxylase (ASPH), with CE1-ASPH sequence homology underpinning tumor recognition and cytotoxicity. Clinically, ASPH is aberrantly upregulated in HCC and correlates with inferred NK cell-associated ADCC activity and improved survival in CE1-seropositive patients. Collectively, these findings reveal a mechanism by which antiviral humoral immunity confers cancer protection through molecular mimicry and highlight anti-CE1 immunity as a potential therapeutic strategy in HCC.

cancer biology↗

bioRxiv2026

MolClaw: An Autonomous Agent with Hierarchical Skills for Drug Molecule Evaluation, Screening, and Optimization

Computational drug discovery, particularly the complex workflows of drug molecule screening and optimization, requires orchestrating dozens of specialized tools in multi-step workflows, yet current AI agents struggle to maintain robust performance and consistently underperform in these high-complexity scenarios. Here we present MolClaw, an autonomous agent that leads drug molecule evaluation, screening, and optimization. It unifies over 30 specialized domain resources through a three-tier hierarchical skill architecture (70 skills in total) that facilitates agent long-term interaction at runtime: tool-level skills standardize atomic operations, workflow-level skills compose them into validated pipelines with quality check and reflection, and a discipline-level skill supplies scientific principles governing planning and verification across all scenarios in the field. Additionally, we introduce MolBench, a benchmark comprising molecular screening, optimization, and end-to-end discovery challenges spanning 8 to 50+ sequential tool calls. MolClaw achieves state-of-the-art performance across all metrics, and ablation studies confirm that gains concentrate on tasks that demand structured workflows while vanishing on those solvable with ad hoc scripting, establishing workflow orchestration competence as the primary capability bottleneck for AI-driven drug discovery.

bioinformatics↗

bioRxiv2026

Polyclonal-Monoclonal Transition in Lung Squamous Cell Carcinoma Evolution

The evolutionary trajectory of lung squamous cell carcinoma (LUSC) remains poorly defined, hindering the development of effective therapies. By integrating genomic and transcriptomic sequencing from human LUSC specimens, we delineated a polyclonal-to-monoclonal evolutionary trajectory during LUSC progression. This evolutionary pattern was corroborated by single-cell RNA sequencing, which revealed consistent tumor cell heterogeneity. Specifically, the SBS5 mutational signature was enriched and correlated with poor prognosis independent of tumor stage. By further utilizing the spontaneous LUSC mouse model to identify key genomic and genetic events in LUSC progression, we observed that the JNK pathway was inhibited and that cytoskeleton-related pathways were dysregulated during LUSC development, and identified the mutations in the JNK pathway (e.g., DACT1) and cytoskeletal regulators (e.g., KIF26A). Collectively, these findings established a polyclonal-monoclonal evolution paradigm for LUSC, potentially regulated by JNK pathways, which could benefit LUSC precision therapeutics.

genomics↗

bioRxiv2026

Impacts of genome architecture on the repeatability of polygenic adaptation

A central but poorly resolved question regards how genome architecture shapes the selection response and repeatability of polygenic adaptation. We addressed this question using Evolve-and-Resequence experiments under rapid salinity decline in two sibling species (clades) of the invasive copepod Eurytemora affinis complex that differ strikingly in chromosome number (15 versus 4). The 4-chromosome genome arose from chromosomal fusions of the ancestral 15-chromosome genome, bringing together coadapted alleles at fusion sites. Across 10-20 generations of selection, both clades adapted to low salinity but followed divergent evolutionary trajectories. The selection lines of the 15-chromosome clade exhibited highly parallel genomic responses, whereas the 4-chromosome clade lines showed delayed and less repeatable responses. Forward genetic simulations revealed that strong synergistic epistasis among beneficial alleles best explained elevated parallelism in the 15-chromosome clade. Additional simulations varying chromosome number and epistasis revealed that strong positive epistasis, combined with high chromosome numbers, enhances parallelism by enabling recombination to assemble coadapted allelic combinations. In contrast, the high starting frequency of beneficial alleles in the 4-chromosome clade lines indicated selection on standing variation, likely acting on alternative linked haplotypes. These findings demonstrate that genome architecture and gene-gene interactions jointly determine the dynamics and predictability of polygenic adaptation.

evolutionary biology↗

bioRxiv2026

An upstream open reading frame represses translation of the neuronal potassium channel KCNQ2

Upstream open reading frames (uORFs) within the 5-untranslated region (5-UTR) of mRNA transcripts can regulate protein translation. Despite widespread prevalence within the human genome, they remain unidentified for many clinically relevant genes. A gene frequently associated with neonatal-onset epilepsy is KCNQ2, which encodes a neuronal voltage-gated potassium channel subunit that functions to dampen neuronal excitability. Heterozygous loss-of-function pathogenic KCNQ2 variants are known to cause a range of neurodevelopmental disorders and epileptic encephalopathies, but there remains an unmet clinical need for patients harboring these variants. We identified a single uORF in KCNQ2 that is highly repressive of protein translation and demonstrated that mutations disabling the uORF start codon enhance translation of encoded potassium channels. Additionally, we show that adenine base editing of the uORF start codon can weaken ribosome engagement at the uORF and enhance translation of the protein in a neuron-like cell line. This study establishes a previously underexplored regulatory feature for KCNQ2 and highlights the importance of understanding uORFs for clinically relevant genes, both for assessing disease risk and therapeutic potential.

molecular biology↗

bioRxiv2026

Comprehensive analysis of TEAD inhibition in meningioma identifies MEK and mTOR inhibition as effective combination therapies against resistant lines.

Meningiomas are the most common primary central nervous system tumors in adults, posing a significant burden to society. Although a large percentage of lower-grade meningiomas are curable by surgery or radiation alone, high-grade and a subset of low-grade meningiomas demonstrate recurrences and complications from treatment. Systemic therapies for meningioma remain ineffective, and no targeted treatments are approved. Despite the central role of YAP1/TAZ-TEAD signaling in NF2-deficient/mutant tumors, no studies have systematically examined TEAD inhibition across molecularly defined meningioma subtypes or investigated mechanisms of resistance in this disease. We have recently shown that YAP1/TAZ signaling is an oncogenic driver of meningioma. Here, using established and patient-derived meningioma cell lines, we demonstrate that genetic ablation of YAP1/TAZ suppresses growth in both NF2 mutant and NF2 wild type cell lines, establishing YAP1/TAZ-TEAD signaling as a shared oncogenic dependency. Pharmacologic TEAD inhibition suppressed growth of benign NF2 mutant and a subset of higher-grade NF2 mutant meningiomas, whereas NF2 wild type meningiomas were generally more resistant. RNA-Seq and Western Blot analysis identified compensatory activation of MEK-ERK, mTOR-S6, and FAK signaling in resistant lines exhibit. Importantly, co-targeting these pathways was able to overcome resistance to TEADi and was superior to MEK/mTOR/FAK inhibition alone. These studies provide a compelling proof-of-concept that TEADi represents a novel therapeutic vulnerability in meningioma and reveal adaptive signaling responses that can be therapeutically exploited.

cancer biology↗

bioRxiv2026

Circulating pre-osteoclasts are primed for osteoclast fate and synovial tissue homing in psoriatic arthritis.

Psoriatic arthritis (PsA) is a complex immune-mediated inflammatory disease with heterogenous clinical features. Osteoclasts have a unique ability to destroy bone, playing key roles in both healthy bone turnover and pathological erosions in arthritis. They are believed to arise from monocytic precursors migrating to inflamed synovial tissue, though the identity of this precursor in humans has remained elusive. Here, we sought to determine whether monocytes home to psoriatic joints and their phenotype. We find that monocytes are recruited to inflamed joints in PsA but not uninvolved or healthy joints, and identify a pre-osteoclast (preOC) cell state derived from classical monocytes. PreOC are transcriptionally distinct from classical monocytes, are enriched for NFACT1, the master regulator of osteoclastogenesis, and form multinucleated osteoclasts in vitro without exogenous RANKL. They are expanded in the circulation of donors with active treatment naive PsA, compared to both healthy controls and those with cutaneous psoriasis only. Finally, using a customised spatial transcriptomics workflow, we identified these cells within human synovial tissue, and radiolabelling confirmed their recruitment from the circulation. These findings highlight the role of systemic immune priming in macrophage pathophysiology.

immunology↗

bioRxiv2026

DNA-triggered AIM2 condensation orchestrates immune activation and regulation

The innate immune sensor AIM2 detects cytosolic DNA and initiates inflammatory responses, yet its activation mechanism remains incompletely understood. Here, we show that AIM2 undergoes liquid-liquid phase separation upon DNA binding, forming dynamic condensates both in vitro and in cells. These condensates serve as platforms for inflammasome and PANoptosome assembly, promoting immune activation across multiple pathways. Direct structural determination from condensates reveals the assembly of active-form ASC filaments. Mechanistically, liquid-phase condensation is governed by multivalent interactions involving different AIM2 domains, including previously uncharacterized regions and species-specific elements. In vitro and in vivo assays show that mutants specifically disrupting condensation impair immune complex assembly, cell death initiation, antimicrobial defense, and intestinal homeostasis. Moreover, AIM2-DNA condensates function as regulatory hubs targeted by host- and pathogen-derived factors to balance immune homeostasis or facilitate immune evasion. These findings establish liquid-phase condensation as a fundamental mechanism of AIM2 activation and a potential therapeutic target.

immunology↗

bioRxiv2026

Telomere-to-telomere gap-free genome assembly integrated with multi-omics uncovers shading mediated regulation of leaf aroma biosynthesis in aromatic crop Pandanus amaryllifolius

Pandanus amaryllifolius is a valuable aromatic crop widely cultivated in tropical forest understories. Here, A telomere-to-telomere, gap-free genome assembly of the Chinese cultivar Taishan Banlan was generated, and the molecular basis underlying shading-mediated regulation of leaf aroma biosynthesis was elucidated for the first time through integrated genomic, transcriptomic, and metabolomic analyses. Volatile metabolomics identified 1599 volatile organic compounds in leaf tissue, with terpenoids as the primary contributors to leaf aroma. Shading modulated the aroma quality of P. amaryllifolius primarily via terpenoid biosynthesis, yielding aroma profiles dominated by sweet, fruity, green, and woody notes. Integrated transcriptomic profiling revealed that terpenoid biosynthesis is co-regulated by structural genes in the MVA/MEP pathways, TPS family members, and key transcription factors, which collectively modulate the biosynthesis and accumulation of the three core differential terpenoids. Our findings provide valuable resources for the targeted genetic improvement and efficient cultivation optimization of P. amaryllifolius.

genomics↗

bioRxiv2026

Multi-component functionalized Bifidobacterium longum hydrogel for multi-target integrated therapy of colitis-associated anxiety and depression

Inflammatory bowel diseases (IBDs) are frequently accompanied by anxiety and depression, largely driven by perturbed gut-brain axis signaling. However, current oral therapies remain constrained by the spatial and functional separation between intestinal inflammation and central nervous system dysfunction. Here, we present a comprehensive gut-brain dual region integrated therapeutic strategy based on functionalized Bifidobacterium longum hydrogel (INPs@BL@Gel), in which baicalin and tyrosine are coordinated with Fe(III) to form infinite coordination polymers (ICPs), coated with inulin, assembled onto Bifidobacterium longum (BL), and subsequently encapsulated within a pH- and matrix metalloproteinase-responsive silk fibroin-gelatin hydrogel. INPs@BL@Gel exhibits high drug-loading, effective gastric protection, inflammation-triggered release, and long-term intestinal colonization. Within the inflamed intestine, BL and components synergistically suppress inflammatory responses, restore gut microbiota homeostasis, and promote intestinal barrier repair through multi-target integrated therapy. Importantly, BL combined with components markedly enhances the production of beneficial neuroactive metabolites such as homovanillic acid and short-chain fatty acids, which integrated regulate neuroinflammation, preserve synaptic function, and facilitate blood-brain barrier repair via the gut-brain axis. In vivo studies demonstrate that INPs@BL@Gel not only exert potent therapeutic efficacy against colitis and effectively alleviate associated depression, but also reshape the gut microbiota and restore barrier integrity, achieving an remarkable comprehensive therapeutic effect. O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/710940v1_fig1a.gif" ALT="Figure 11"> View larger version (59K): org.highwire.dtl.DTLVardef@1a831f3org.highwire.dtl.DTLVardef@1676617org.highwire.dtl.DTLVardef@15f99c1org.highwire.dtl.DTLVardef@1677cc4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOScheme 1.C_FLOATNO (a) Schematic diagram of the design and preparation of functionalized Bifidobacterium longum hydrogel. (b) Exploration of the mechanism of INPs@BL@Gel in treating colitis-associated anxiety and depression through a dual-site multi-target synergistic strategy. C_FIG

pathology↗

bioRxiv2026

Ancestral secretory programs underlie the evolution of morphological innovations across Spiralia

Understanding how morphological innovation arise from ancestral genetic and cellular systems remains a major challenge in evolutionary biology. Molluscan shells represent one of the most diverse morphological novelties within Spiralia and have been central to the ecological and evolutionary diversification of molluscs. However, the cellular basis of shell formation and the evolutionary origin of shell-forming cell types remain poorly understood. Here, we present a single-cell transcriptomic atlas of the Pacific oyster (Crassostrea gigas) mantle and show that molluscan shell-forming cell types are evolutionarily recent innovations built upon ancestral epithelial secretory systems of spiralians. We identify five spatially segregated shell-forming epithelial cell types, and demonstrate that larval and adult shell-forming cells are developmentally independent and characterized by transcriptomes enriched for evolutionarily young genes. Cross-species cell-type comparisons further reveal that oyster shell-related genes are embedded within conserved epithelial and secretory programs across spiralians. Together, we propose that a substantial genetic foundation for shell formation was already present in the last common ancestor of Spiralia, and that molluscan shell diversity arose through repeated co-option of ancestral genetic programs coupled with novel genes. Our study provides a framework for understanding how ancient cellular architectures can be repeatedly reconfigured to generate morphological novelty during evolution.

evolutionary biology↗

bioRxiv2026

Multi-omic profiling of human and mouse dorsal root ganglia enables targeted gene delivery to nociceptors

Chronic pain conditions are often driven by hyperexcitability of nociceptors, the peripheral sensory neurons that detect noxious stimuli. Recent single-cell transcriptomic studies have begun to clarify the molecular identity of distinct peripheral sensory neuron subtypes, but tools that restrict transgene expression to nociceptors while sparing other dorsal root ganglion (DRG) subtypes remain limited. Here, we combined single-nucleus multi-omic profiling of human and mouse DRG with in vivo AAV enhancer screening to identify cis-regulatory elements that drive biased AAV expression in mouse DRG nociceptors and human iPSC-derived nociceptors. We then validated that an enhancer AAV designed to express Kir2.1 preferentially in nociceptors reduces DRG neuronal excitability. Leveraging these multi-omic datasets, we trained a sequence-based model to decode the cis-regulatory logic of nociceptors, enabling both the prioritization of native candidate elements and the design of synthetic enhancers with a range of nociceptor targeting properties. Together, these cross-species multi-omic resources define conserved DRG regulatory programs and provide a viral toolkit for pain research with potential translational applications for patients with refractory pain.

neuroscience↗

bioRxiv2026

Lung microvascular rarefaction impairs pulmonary gas exchange and exacerbates heart failure with preserved ejection fraction

BackgroundDyspnea and exercise intolerance are the primary clinical symptoms of heart failure. Heart failure patients experience frequent hypoxemic episodes, yet underlying mechanisms and relevance remain poorly understood. In a cohort of heart failure patients and multiple animal models, we identify pulmonary capillary rarefaction driven by excessive autophagy in endothelial cells as a novel mechanism of hypoxemia and cardiac disease progression. MethodsA cohort of heart failure with preserved ejection fraction (HFpEF) patients was analyzed for parameters of left ventricular (LV) dysfunction and pulmonary gas exchange. Morphological and cellular mechanisms of impaired pulmonary oxygenation were assessed in three animal models of heart failure, namely two HFpEF models, SU5416-treated ZSF1 obese rats and high fat diet/L-NAME treated mice, and in rats subjected to aortic banding. Lung microvascular rarefaction was quantified by micro-computed tomography, stereology, flow cytometry and dye efflux. Cellular mechanisms of capillary loss were analyzed by single-cell transcriptomics, electron microscopy and immunofluorescence, and in mice with endothelial-specific deletion of the autophagy gene Atg7 (Atg7EN-KO). ResultsIn 234 HFpEF patients, advancing NYHA class was associated with progressive worsening of arterial oxygen saturation at rest and during exercise and a reduced lung diffusing capacity. Impaired gas diffusion correlated with indices of LV diastolic dysfunction. Impaired oxygenation and reduced exercise capacity were similarly evident in animal models of left heart disease, which showed a distinct loss of pulmonary microvessels and capillaries. Lung microvascular endothelial cells in HFpEF showed characteristics of increased autophagic flux and apoptosis. Relative to their wild type HFpEF controls, Atg7EN-KO mice had less capillary loss, restored normoxemia, improved exercise tolerance, and mitigated LV diastolic dysfunction. Additional studies in HFpEF mice corroborated the functional relevance of impaired gas exchange for the progression of left heart disease by demonstrating that additional hypoxia aggravated, whereas moderate hyperoxia improved LV function. ConclusionOur findings identify pulmonary microvascular rarefaction as a novel pathomechanism in heart failure that i) contributes to dyspnea and exercise intolerance, ii) impairs pulmonary gas exchange and iii) accelerates LV disease progression. Strategies targeting this axis such as moderate oxygen therapy may mitigate cardiopulmonary morbidity in heart failure. Clinical Trial RegistrationRegistered in the DRKS (Deutsches Register fur klinische Studien) as trial# DRKS00032974 at https://drks.de/search/en/trial/DRKS00032974.

physiology↗

bioRxiv2026

Co-evolution of Oncogenic KRAS Signaling and LILRBhigh Macrophages Drives Pancreatic Cancer Recurrence

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied by expansion of basal-like malignant cell states. In parallel, we identified an immunosuppressive macrophage population marked by high LILRB expression that spatially co-localized with KRAS-activated tumor cells. Functional studies showed that LILRB4+ macrophages enhanced tumor cell plasticity and progression, whereas inhibition of macrophage LILRB4 suppressed these phenotypes. Notably, a first-in-class human anti-LILRB4 antibody reduced macrophage-driven tumor traits, and dual targeting of KRAS signaling and LILRB4 achieved superior tumor control in macrophage-containing mouse models. These findings reveal a co-evolved tumor-immune niche underlying PDAC recurrence and nominate the KRAS-LILRB4 axis as a therapeutic vulnerability.

cancer biology↗

bioRxiv2026

Connectome lateralization in autism across the first 14 years: heterogeneity related to developmental stage, hemisphere, and pathophysiology

Hemispheric lateralization is fundamental feature to neurodevelopment, yet its dynamic evolution in autism across childhood and underlying molecular mechanisms remain unknown. Thus, using a large-scale resting-state fMRI dataset (n = 1553, ages 1-14), we investigated developmental heterogeneity in connectome lateralization. At the group level, abnormalities in dynamic connectome lateralization strength (DCLS) progressed from focal patterns in early childhood ([≤] 6 years) to widespread distributions by late childhood ([≤] 14 years), independent of symptom severity. The late-stage patterns were validated using the ABIDE dataset (n=153). Late childhood also showed marked increases in inter-individual heterogeneity. These alterations were significantly associated with clinical phenotypes, transcriptomic profiles, and multiple neurotransmitter systems, with distinct patterns across childhood groups. Our findings reveal a developmentally dynamic trajectory of connectome lateralization in autism and highlight late childhood as a critical window for stage- and individual-specific interventions tailored to substantial individual heterogeneity.

neuroscience↗

bioRxiv2026

ALKBH5 Promotes Hepatic Gluconeogenesis via m6A-mediated Stabilization of Ogt mRNA

Excessive hepatic glucose production is a hallmark of fasting hyperglycemia in type 2 diabetes mellitus, yet the epitranscriptomic mechanisms that sustain this dysregulation remain incompletely understood. Here, we show that dexamethasone/forskolin-induced gluconeogenic activation triggers widespread remodeling of RNA m6A methylation in mouse primary hepatocytes. Among the m6A regulators examined, the demethylase ALKBH5 is robustly induced both in vitro and in fasted livers. This induction is mediated by the glucocorticoid receptor, which binds to the Alkbh5 promoter and activates its transcription. Functionally, ALKBH5 overexpression enhances gluconeogenic gene expression and glucose production, whereas both global and hepatocyte-specific Alkbh5 knockout mice exhibit suppressed hepatic gluconeogenesis. Mechanistically, we identify Ogt as a primary downstream target, defining an ALKBH5-OGT epitranscriptomic axis in hepatocytes. ALKBH5 demethylates and stabilizes Ogt mRNA, thereby elevating OGT expression and promoting gluconeogenic gene expression. Consistently, the pro-gluconeogenic effects of ALKBH5 are largely abrogated by OGT knockdown. Finally, pharmacological inhibition of ALKBH5 with 18l effectively improves glucose tolerance and suppresses hepatic gluconeogenesis in both wild-type and db/db mice. Together, these findings reveal a glucocorticoid-responsive epitranscriptomic mechanism whereby ALKBH5 stabilizes Ogt mRNA to drive gluconeogenesis and highlight ALKBH5 as a promising therapeutic target for type 2 diabetes mellitus.

molecular biology↗