Biology subjects

Lu, X.

Publications and source records attributed to Lu, X..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Fertility recovery after combined adriamycin, bleomycin, vinblastine and dacarbazine chemotherapy in mice

BackgroundWith combined adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy and radiotherapy, most of Hodgkin lymphoma (HL) patients were cured. The effect of ABVD treatment on ovarian reserve and fertility has not been fully characterized, and whether fertility preservation is required is controversial and not empirically known. MethodsEight-week-old female mice were injected intravenously with saline solution or ABVD for 4 weeks, respectively. Estrous cycles, level of serum anti-Mullerian hormone (AMH), body weight and ovary weight were recorded. Ovarian tissue structure and the number of follicles at each stage were analysed. IVF assay and natural mating trials were performed. Finally, transcriptome sequencing of ovarian tissue was conducted. ResultsMost mice completely lost their estrous cycle soon after ABVD injection. After 4 cycles of treatments, the body weight gain and gross ovarian weight were significantly lower than those of the control. However, estrous cycles were returned to normal at 4 weeks after ABVD discontinuation. Serum AMH and the numbers of primordial follicles were significantly increased compared to controls. ABVD withdrawal did not affect the rate of cleavage or blastocyst formation in IVF assays. Furthermore, the mice were fertile and there was no significant difference in offspring weight, but the number of offspring in the ABVD discontinuation group was smaller compared with the controls. Transcriptome analyses revealed that the JAK/STAT pathway, which is involved in the inhibition of primordial follicles activation and apoptosis, was upregulated in ABVD-treated ovaries, whereas few gene expressions were altered 4 weeks after ABVD withdrawal. ConclusionsThe ovarian reserve and reproductive function can be recovered after ABVD treatment, and combined ABVD treatment for a short time has a beneficial effect on the ovarian reserve, which can be used to provide a basis for guiding fertility preservation decision-making for HL patients. Statements and DeclarationsThe authors declare no competing interests.

developmental biology↗

bioRxiv2025

Differential Regulation of Hepatic Macrophage Fate by Chi3l1 in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression involves the replacement of protective embryo-derived Kupffer cells (KCs) by inflammatory monocyte-derived macrophages (MoMFs), yet the regulatory mechanisms remain unclear. Here, we identify chitinase 3-like 1 (Chi3l1/YKL-40) as a critical metabolic regulator of hepatic macrophage fate. We observed high expression of Chi3l1 in both KCs and MoMFs during MASLD development. Genetic deletion of Chi3l1 specifically in KCs significantly exacerbated MASLD severity and metabolic dysfunction, whereas MoMF-specific Chi3l1 deletion showed minimal metabolic effects. Mechanistic studies revealed that this cell type-specific regulation arises from differential metabolic requirements: KCs display elevated glucose metabolism compared to MoMFs. Chi3l1 directly interacts with glucose to inhibit its cellular uptake, thereby selectively protecting glucose-dependent KCs from metabolic stress-induced cell death while having negligible effects on less glucose-dependent MoMFs. These findings uncover a novel Chi3l1-mediated metabolic checkpoint that preferentially maintains KCs populations through glucose metabolism modulation, providing important new insights into the pathogenesis of MASLD and potential therapeutic strategies targeting macrophage-specific metabolic pathways.

molecular biology↗

bioRxiv2025

GenVS TBDB: An Open AI-Generated andVirtual Screened Small-Molecule Database for Tuberculosis Drug Discovery

Tuberculosis (TB) remains a leading global health threat, with over 10 million new cases and 1.25 million deaths reported in 2023. Current TB therapies rely on a limited drug repertoire and prolonged treatment courses that have changed little in four decades. Here, we present GenVS-TBDB, a target-aware AI-generated and virtual-screened small-molecule database, which expands the chemical space against Mycobacterium tuberculosis (M.tb) essential proteins. We first identified 460 probable small-molecule binding pockets across 377 essential M.tb proteins by integrating multiple sources. Then, by leveraging the target-aware molecule generative model, over 1.2 million novel small molecules tailored to these pockets were produced. The key physicochemical properties were computed for all compounds to ensure medicinal chemistry tractability. These compounds were also evaluated using molecular docking and anti-TB specific graph neural network model, yielding binding propensity ranking and whole-cell activity prioritization for each target. To substantiate the integrated AI-driven workflow for anti-TB discovery, 30 compounds were obtained, including 22 AI-designed molecules synthesized de novo and 8 commercially available analogs. In validation, 2 synthesized compounds demonstrated significant thermal stabilization of FtsZ, confirming target engagement. 6 compounds exhibited cellular inhibition below 50 {micro}M, the most potent at 12 {micro}M. Furthermore, GDI-11785 showed binding to the cell wall biosynthesis pathway with 35 {micro}M cellular activity, establishing a promising starting point for tuberculosis drug discovery. Our findings contribute a significant library of bioactive molecules which may hasten the preliminary phase of tuberculosis drug discovery. The GenVS-TBDB small library is publicly accessible and can be downloaded freely at https://datascience.ghddi.org/database/view.

pharmacology and toxicology↗

bioRxiv2025

Systemic trafficking of mRNA lipid nanoparticle vaccine following intramuscular injection generates potent tissue-specific T cell response

The mRNA lipid nanoparticles (LNPs) represent a new generation of vaccine carriers designed to elicit potent immune responses against infectious diseases and cancer. Despite the clinical success and rapid advancements in mRNA LNP technologies, the trafficking patterns of LNPs after intramuscular (i.m.) administration and the subsequent tissue-specific immunological effects have not been systematically characterized. Here, we report that trafficking of mRNA LNPs to different organs following i.m. injection is crucial for the induction of tissue-specific immunity beyond systemic immune response, particularly in tissue-resident CD8+ T cell generation, which is important for localized defense. By fine-tuning the composition of mRNA LNPs, trafficking patterns to systemic organs can be modulated, which can alter the resulting tissue-specific immune response. Formulations with a greater ability to enter the bloodstream can preferentially localize and transfect cells in specific organs like the liver, elicit stronger tissue-specific CD8+ T cell immune responses, and achieve enhanced efficacy in a liver tumor model. These findings highlight the potential to tailor mRNA LNP compositions to modulate trafficking following i.m. injection, thereby providing novel strategies for designing tissue-specific vaccines. Such strategies are particularly valuable for organ-specific diseases like cancer and infectious diseases, where tissue targeting and long-lasting immunity are essential for therapeutic success.

bioengineering↗

bioRxiv2025

Deconvoluting single-cell transcriptomics reveals cellular programs regulated by cell-cell communication in colorectal cancer

Cells within a tissue microenvironment communicate through intricate cell-cell communication (CCC) networks. In this meta-analysis of eight single-cell cohorts encompassing 153 patients and 279 samples, we advance the understanding of CCC networks in colorectal cancers through a novel analytical framework. Employing hierarchical topic modeling, we identify gene expression modules (GEMs) that mirror single-cell signaling states, crucial for deciphering the complexity of intercellular interactions. By applying causal discovery methods, we systematically uncover GEMs likely regulated by ligand-receptor signaling and cross-cell-type communication. This analysis reveals cross-cell-type CCC programs, marked by highly correlated GEMs across various cell types, shedding light on the intricate CCC networks within the tumor microenvironment. Spatial transcriptomics further validate these findings by demonstrating the co-localization of GEMs within CCC programs in distinct spatial domains, emphasizing the spatial dynamics of tumor intercellular communication. Our interactive website (http://44.192.10.166:3838/) and analytical framework equip researchers with powerful tools to explore these complex mechanisms, potentially uncovering novel drug targets and refining strategies for precision immunotherapies. This comprehensive study not only presents a detailed catalog of CCC networks driven by ligand-receptor interactions in colorectal cancer but also highlights the significance of integrating multi-sample and patient data to unravel the molecular underpinnings of cancer communication pathways.

bioinformatics↗

bioRxiv2025

Influence of Macrocyclization Strategies on DNA-Encoded Cyclic Peptide Libraries

Discovery of cyclic peptide hits using DNA-encoded libraries (DELs) has recently been extensively researched, with significant efforts directed toward developing DEL-compatible macrocyclization methods. To investigate how different cyclic linkers influence DEL selection outcomes, we constructed eight distinct sub-libraries and screened them against two protein targets, MDM2 and GIT1, resulting in two representative yet contrasting scenarios. Validation studies for MDM2 revealed that structural similarity patterns observed across multiple sub-libraries could enhance confidence in the authenticity of identified hits. Notably, cmp-10 demonstrated potent inhibitory activity, exhibiting an inhibition constant of 11 nM. In contrast, selections against GIT1 produced discrete enrichment patterns. From these outcomes, two exemplary compounds were selected and validated through both on-DNA and off-DNA modes. cmp-17 was confirmed to bind specifically to the desired binding pocket, displaying a dissociation constant of 1.22 M. Furthermore, ITC experiments using mutant GIT1 proteins (GIT1L271A/L279A and GIT1L271L/L279L) provided additional insights into the mechanism by which cmp-17 disrupts the interaction between GIT1 and {beta}-Pix.

biochemistry↗

bioRxiv2025

A zebrafish immunodeficiency model induced by the combination of Tacrolimus and Everolimus for rapid assessment of immune-enhancing agents

A methodology for the assessment of the immune-enhancing effects of various substances within a period of 5 days was reported. Experimentally, it was determined that the continuous treatment of Tacrollimus (0.5 ng/mL) and Everolimus (5 g/mL) on zebrafish from 48 hpf to 120 hpf was sufficient to establish an immunodeficient model. The results showed that the model exhibited a significant reduction in the number of immune cells (thymocytes, myeloid cells, and macrophages) and a greater than 50% decrease in the expression of immune-related genes (itk, hexb, cpa5, isg15, rsad2). Astragalus powder can effectively increase the content of thymic T cells and macrophages, but its effect on myeloid cells is limited. Ganoderma lucidum spore powder had the most obvious influence on macrophages, with limited impact on thymus cells and myeloid cells. Royal jelly showed a significant effect on thymus T cells and macrophages, but its effect on myeloid cells was limited. Bailing capsule can significantly increase the content of myeloid cells and thymus T cells, while its effect on macrophages was limited. The study showed immune indexes varied in recovery with different immunomodulators versus the model group, suggesting they may act via distinct mechanisms. Summary StatementA robust immune system is vital to overall health and quality of life. Recent years have witnessed surging development of immune-boosting pharmaceuticals, nutraceuticals, and functional foods. However, an easy-to-use, rapid and intuitive immunity assessment framework is still missing. Here, a methodology for the assessment of the immune-enhancing effects of various substances within a period of 5 days was reported.

immunology↗

bioRxiv2025

Haploinsufficiency of eNOS mitigates beneficial effects of maternal exercise on fetal heart development during pregestational diabetes

BackgroundPregestational diabetes (PGD) increases congenital heart defect (CHD) risk over five-fold. Maternal exercise enhances endothelial nitric oxide synthase (eNOS) activity, benefiting embryos, though its causal role remains unclear. This study investigated eNOSs role in maternal exercise-mediated protection of fetal heart development in a PGD mouse model. MethodsPGD was induced in eNOS+/- or wild-type (WT) female mice via streptozotocin before breeding with WT or eNOS+/- males. Pregnant females had access to a running wheel for voluntary exercise or remained sedentary. Fetuses were collected at embryonic day (E) 18.5 for genotyping and CHD assessment. E12.5 hearts were analyzed for proliferation, apoptosis, oxidative stress, and eNOS protein levels. ResultsMaternal exercise normalized litter size and mortality rates in offspring of diabetic eNOS+/- females but did not reduce CHD incidence in offspring of WT or eNOS+/- females with PGD. CHDs included septal defects, double outlet right ventricle, and valve defects. Exercise increased coronary artery density but not capillary density. Proliferation deficits at E12.5 were restored by exercise, yet oxidative stress remained elevated. Maternal exercise in eNOS+/- dams during PGD did not significantly change eNOS protein levels in both eNOS+/+ and eNOS+/- fetal hearts. Offspring genotype did not impact CHD incidence, cell proliferation, apoptosis or oxidative stress. ConclusionsMaternal exercise does not prevent CHDs in PGD offspring of eNOS+/- mice. Its ability to mitigate PGD-induced oxidative stress is eNOS-dependent and essential for improving heart morphology. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/647329v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@4c9e4forg.highwire.dtl.DTLVardef@2d60fforg.highwire.dtl.DTLVardef@13b2d72org.highwire.dtl.DTLVardef@249a0c_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2025

RNA polymerase II O-GlcNAcylation promotes nuclear entry to drive transcription

O-GlcNAcylation of RNA Polymerase II (RNA Pol II) was described in 1993 and here we wanted to probe the functional significance of this modification. O-GlcNAc transferase (OGT) is the sole enzyme performing nucleo-cytoplasmic O-GlcNAcylation. The role of RNA Pol II O-GlcNAcylation has remained enigmatic partly due to the lack of reagents selectively recognizing the O-GlcNAcylated polymerase. We developed a novel approach, wheat germ agglutinin (WGA) lectin-based enrichment for O-GlcNAcylated proteins followed by traditional ChIP for RNA Pol II, to identify chromatin-binding sites of the O-GlcNAcylated RNA Pol II. We termed this technique as wChIP and used it to demonstrate that the O-GlcNAcylated RNA Pol II is enriched to the promoters of highly expressed genes. RNA Pol II has a repetitive c-terminal domain (CTD) of YSPTSPS, which is heavily post-translationally modified. Using structural modeling and WGA pulldown-experiments, we identify Ser-5 as a CTD site that is dynamically modified by OGT. Mass spectrometry-based detection of proteins that recognize CTD that is O-GlcNAcylated on Ser-5 identified nuclear transport protein, karyopherin subunit beta 1 (KPNB1), as a reader protein for this modification. Functionally, high activity of both OGT and KPNB1 is required for the efficient entry of RNA Pol II to nucleus and chromatin. OGT and KPNB1 are significantly co-expressed in prostate cancer tissue, and their combined inhibition is more toxic to prostate cancer cells than normal prostate cells. We propose that RNA Pol II O-GlcNAcylation promotes entry to nucleus, and this could integrate metabolic information to regulate global transcription.

cancer biology↗

bioRxiv2025

DiCE: Differential Centrality-Ensemble Analysis Based on Gene Expression Profiles and Protein-Protein Interaction Network

Uncovering key genes that drive diseases and cancers is crucial for advancing understanding and developing targeted therapies. Traditional differential expression analysis often relies on arbitrary cutoffs, missing critical genes with subtle expression changes. Some methods incorporate protein-protein interactions (PPIs) but depend on prior disease knowledge. To address these challenges, we developed DiCE (Differential Centrality-Ensemble), a novel approach that combines differential expression with network centrality analysis, independent of prior disease annotations. DiCE identifies candidate genes, refines them with an information gain filter, and reconstructs a condition-specific weighted PPI network. Using centrality measures, DiCE ranks genes based on expression shifts and network influence. Validated on prostate cancer datasets, DiCE identified genes over-represented in key pathways and cancer fitness genes, significantly correlating with disease-free survival (DFS), despite DFS not being used in selection. DiCE offers a comprehensive, unbiased approach to identifying disease-associated genes, advancing biomarker discovery and therapeutic development. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/638654v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1ce9b81org.highwire.dtl.DTLVardef@14352e1org.highwire.dtl.DTLVardef@f63caeorg.highwire.dtl.DTLVardef@a0086_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Novel Probe Design for Multi-Gene Detection Enabled by Cleavage and Capillary Electrophoresis

Nucleic acid sequences carry the most fundamental information about life, and gene detection plays a crucial role in studying and applying gene function. Here, we present a novel probe design that utilizes probe cleavage and capillary electrophoresis for gene detection, termed ProbeCE which detects genes by measuring the relative fluorescence signal intensity. Through the evaluation of probes with varying lengths and modifications, ProbeCE is believed to support the simultaneous detection of hundreds of genes. Additionally, the assessment of low-concentration samples has demonstrated the high sensitivity of the ProbeCE method. Compared to the conventional amplification product capillary electrophoresis (AmpCE) method, this new approach significantly increases detection throughput while simplifying primer design and enhancing specificity. In addition, ProbeCE is less expensive than current medium- or high-throughput sequencing for detecting large numbers of known genes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/643483v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@188decborg.highwire.dtl.DTLVardef@dae443org.highwire.dtl.DTLVardef@c01a55org.highwire.dtl.DTLVardef@d653_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Red Light-Activated Reversible Inhibition of Protein Functions by Assembled Trap

Red light offers strong tissue penetration and low phototoxicity, making it an attractive option for optogenetic applications. However, the available red light-inducible optogenetic tools are rather limited. Here, we present a novel red light-induced protein clustering system, namely R-LARIAT (Red Light-Activated Reversible Inhibition by Assembled Trap), that controls protein functions in a spatiotemporal manner. Our system capitalizes on the rapid and reversible binding of LDBs (nanobodies-based dimerization binders) to a bacterial phytochrome DrBphP, which uses a mammalian endogenous biliverdin chromophore to absorb red light. An anti-GFP nanobody fused with LDBs allows this method to quickly trap a wide variety of GFP-tagged proteins into light-induced protein clusters. Strikingly, our system exhibits an excellent performance in clustering efficiency with high light sensitivity and stability, it can function even when shielded by multiple glass plates. By utilizing the R-LARIAT system to trap and sequester tubulin, cell cycle progression can be blocked in HeLa cells. Therefore, the R-LARIAT system takes advantage of red light with greater tissue penetration and holds the potential to precisely control protein functions in living organisms.

cell biology↗

bioRxiv2025

Comparative Analysis of 3D Culture Methodologies in Prostate Cancer Cells

Three-dimensional (3D) cell culture models are increasingly utilized in cancer research to better replicate in vivo tumor microenvironments. This study examines the effects of different 3D scaffolding materials, including Matrigel, GelTrex, and the plant-based GrowDex, on prostate cancer cell lines, with a particular emphasis on neuroendocrine prostate cancer (NEPC). Four cell lines (LNCaP, LASCPC-01, PC-3, and KUCaP13) were cultured in these scaffolds to evaluate spheroid formation, cell viability, and gene expression. The results revealed that while all scaffolds supported cell viability, spheroid formation varied significantly: Matrigel promoted the most robust spheroids, especially for LASCPC-01, whereas GrowDex exhibited limitations for certain cell lines. Gene expression analysis indicated a consistent reduction in androgen receptor (AR) expression in LNCaP cells across all scaffolds, suggesting a potential shift towards a neuroendocrine phenotype. However, the expression of neuroendocrine markers varied depending on the scaffold and culture method, with the mini-domes method in Matrigel leading to decreased expression of both castration-resistant prostate cancer (CRPC) and NEPC markers. These findings highlight the scaffold-dependent variability in 3D culture outcomes and emphasize the need for standardized methodologies to ensure consistency and relevance in prostate cancer research. HighlightsO_LIComparing of Matrigel, GelTrex, and GrowDex in 3D prostate cancer culture C_LIO_LIIdentifying scaffold-dependent spheroid formation and gene expression shifts C_LIO_LIObserving consistent AR reduction and variable neuroendocrine marker changes C_LIO_LIHighlighting the need for standard 3D culture methods in cancer studies C_LI

cancer biology↗

bioRxiv2025

FACED 2.0 enables large-scale voltage and calcium imaging in vivo

Monitoring neuronal activity at large scale and high spatiotemporal resolution is crucial for understanding information processing within the brain. We optimized a kilohertz-frame-rate two-photon fluorescence microscope with all-optical megahertz line-scan rate to achieve ultrafast imaging across large areas and volumes at subcellular resolution. Applying this technique to voltage and calcium imaging in vivo, we demonstrated simultaneous recording of voltage activity over 200 neurons and calcium activity over 14,000 neurons.

neuroscience↗

bioRxiv2025

Cryo-ET of IgG bivalent binding on SARS-CoV-2 provides structural basis for antibody avidity

The bivalent nature of IgG enhances its neutralization potency against enveloped viruses; however, on-virion structural details of IgG bivalent binding with antigens remain elusive. Here we used cryo-ET to investigate how two potent IgGs P17 and S309 interact with S-trimers on the SARS-CoV-2 surface. We found that these antibodies exploit the mobility of S-trimers to form diverse bivalent binding patterns. P17 stabilizes S-trimers in a one-RBD-up conformation and gathers S-trimer into linear multimers within minutes, whereas S309 primarily forms circular S-trimer assemblies that extend into lattice-like structures. Additionally, both IgGs can facilitate inter-virion coupling through bivalent binding of opposing S-trimers. These findings provide a structural basis for understanding IgG avidity and offer insights for antibody engineering and vaccine design.

biophysics↗

bioRxiv2025

Unveiling Candidate Drivers in Cancer Progression Using Somatic-IV Analysis

MotivationIdentifying causal drivers of cancer progression is crucial for developing effective anti-cancer therapies. However, disentangling causality from correlation remains challenging due to confounding factors within the complex genetic and transcriptomic landscapes of cancer. ResultsTo address this challenge, we introduce the Somatic Instrumental Variable analysis (Somatic-IV), which integrates genetic, transcriptomic, and clinical outcome data to identify candidate driver genes likely playing a causal role in disease progression. Somatic-IV estimates genetic-exposure and genetic-outcome associations, utilizing MR-Egger regression to estimate bias-reduced causal effects. We assessed the statistical properties and performance of Somatic-IV through a simulation study and demonstrated its utility in pancreatic adenocarcinoma (PDAC) and colorectal cancer (CRC). Our analysis identified ZBED2 and CSNK2A2 as likely drivers of PDAC and CRC cancer progression, respectively. Somatic-IV is a novel approach for generating target hypotheses and guiding the development of effective therapies for cancer patients. Availability and implementationThe Somatic-IV package is available at: https://github.com/wzhang1984/Somatic_IV_package

bioinformatics↗

bioRxiv2025

Predicting Mutation-Induced Relative Protein-Ligand Binding Affinity Changes via Conformational Sampling and Diversity Integration with Subsampled Alphafold2 in Few-Shot Learning

Predicting the impact of mutations on protein-ligand binding affinity is crucial in drug discovery, particularly in addressing drug resistance and repurposing existing drugs. Current structure-based methods are constrained by their dependence on known protein-ligand complex structures. The absence of structural data for mutated proteins, along with the potential of mutations to modify protein conformational states, brings challenges for reliable predictions. The downstream application of conformational sampling of Alphafold, such as the prediction of binding free energy changes induced by mutation, has not been fully explored. To tackle the challenge, we propose a few-shot learning approach that integrates AlphaFold2 subsampling, ensemble docking, and Siamese learning to predict the relative binding affinity changes induced by mutations. We validate our approach for predicting binding affinity changes in 31 variants of the mutated Abelson tyrosine kinase (ABL). The conformation ensembles for each ABL variant are generated using AlphaFold2 subsampling. The most likely conformational states are selected by Gaussian fitting to construct the pairwise structural inputs and compute relative binding energies. Then the relative binding affinities are derived by averaging the values predicted by the Siamese learning model across the constructed conformational pairs. By benchmarking on the Tyrosine kinase inhibitors (TKI) dataset and the direct binding affinity using the refined set of PDBbind database, our proposed approach achieves an increased Spearman correlation coefficient for five out of six TKI molecules across 31 mutants when estimating relative binding affinities. Although the proposed method is validated on the ABL, it can be transferred and applied to other drug-target interaction predictions when the conformational flexibility of proteins needs to be considered. We anticipate the approach will be valuable for predicting binding energy changes induced by mutations in proteins or ligands, facilitating drug discovery efforts.

bioinformatics↗

bioRxiv2025

KYLO-0603, a novel liver-targeting, thyroid hormone recep-tor-β agonist for the treatment of MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. Kylo-0603 is a novel agonist for the thyroid hormone receptor {beta} (THR-{beta}) that has been developed by merging the structures of three acetylgalactosamine (GalNAc)-modified ASPGR ligands with a triiodothyronine (T3) analog. This unique design allows for both THR-{beta} activation and targeted delivery to hepatocytes, significantly reducing the risk of adversed effects related to increased systemic thyroid hormone-like effects. Additionally, it effectively lowers serum cholesterol by as much as 69.2% and low-density lipoprotein cholesterol (LDL-C) levels by up to 88.2% in the MASH mouse model. Meanwhile, Kylo-0603 was shown to reduce steatosis by up to 1.3 points (P < 0.001), inflammation by 1.8 points (P < 0.0001), and ballooning by 0.8 points (P < 0.01). The non-alcoholic steatohepatitis (NASH) activity score (NAS) decreased by up to 3.7 points (P < 0.0001), and the fibrosis score dropped by 0.6 points (P < 0.05). These findings suggest that Kylo-0603 is effective in enhancing liver tissue NASH status and inhibiting fibrosis progression. In summary, Kylo-0603, as a highly both tissue and target selective and low-toxicity THR-{beta} agonist, shows significant promise for treating MASH and is likely to emerge as a new therapeutic option for patients with this condition.

biochemistry↗