Biology subjects

Chen, Z.

Publications and source records attributed to Chen, Z..

At least 199 records · Page 11Linked to original sources

bioRxiv2025

Benchmarking Perturbation Tools for the Noncoding Genome

Deciphering the functionality of the noncoding genome which includes important cis-regulatory elements (CREs) and transcribed noncoding RNA genes remains technically challenging. Here, using massively parallel genetic screening, we systematically benchmark the performance of five representative loss-of-function perturbation tools, including single guide RNA (gRNA) mediated SpCas9 cleavage or CRISPR interference, and paired gRNA (pgRNA) involved dual-SpCas9, Big Papi (paired SpCas9 and SaCas9) or dual-enAsCas12a fragment deletion methods, in decoding the roles of the noncoding genome. For targeting CREs such as enhancer, dual-SpCas9 outperforms other methods with superior efficiency of destroying functional genomic regions. For perturbing noncoding RNA genes, in addition to dual-SpCas9, other RNA-targeting methods such as RNA interference are recommended to discriminate transcript-dependent or -independent roles. A deep learning model DeepDC with associated web server is built to facilitate optimal dual-SpCas9 pgRNA design for efficiently deleting a genomic fragment. Together, our work provides practical guidance on selecting appropriate loss-of-function tools to resolve the functional complexity of the noncoding genome.

genetics↗

bioRxiv2025

CAMK2-NR4A1 signaling initiates metabolic substrate switching to induce heart failure with reduced ejection fraction

Heart failure with reduced ejection fraction (HFrEF) is marked by a shift in cardiac energy metabolism from fatty acid oxidation to glucose utilization. This "fuel switch" promotes accumulation of glucose byproducts that modify calcium-handling proteins and impair cardiac function, yet the initiating signals remain unclear. We identify Ca2+/calmodulin-dependent protein kinase II (CAMK2) as an upstream regulator that triggers pathological substrate switching leading to cardiac systolic dysfunction. Dynamic [18F]FDG-PET imaging showed a six-fold increase in myocardial glucose uptake after pressure overload in control mice, but not in cardiomyocyte-specific Camk2d/Camk2g double knockouts (cDKO), even before functional decline. cDKO hearts retained lipid reserves, indicating preserved fatty acid metabolism. Transcriptomics revealed strong CAMK2-dependent induction of Nr4a1 and early repression of genes for fatty acid uptake and {beta}-oxidation preceding upregulation of genes for glucose utilization. Cardiomyocyte-specific Nr4a1 knockout mice closely mimicked the metabolic protection seen in cDKO, while NR4A1 overexpression in human iPSC-derived cardiomyocytes suppressed fatty acid metabolism. NR4A1 directly bound and repressed the FATP1 (Slc27a1) promoter, thereby secondarily enhancing glucose utilization. Together, these findings define a CAMK2-NR4A1 signaling axis that drives lipid depletion and metabolic remodeling, establishing it as a causal mechanism linking energy substrate switching to HFrEF.

physiology↗

bioRxiv2025

CDK4/6 Inhibition Reverses MEIS2 Suppression of CRL4 to Enhance Immunomodulatory Drug Therapy in Multiple Myeloma

MEIS2 was identified biochemically as a substrate of cereblon (CRBN), a receptor of the CRL4CRBN E3 ubiquitin ligase required for the anti-myeloma activity of immunomodulatory drugs (IMiD)s and CELMoDs. However, its function in myeloma is unknown. We discovered that MEIS2 is aberrantly expressed in bone marrow myeloma cells (BMMC)s, and that high MEIS2, CDK4 or CDK6 and low CRBN expression predisposes patients to inferior overall survival in IMiD therapy. Inhibition of CDK4/6 (CDK4/6i) reprograms BMMCs for IMiD vulnerability ex vivo that mimics patients response to IMiDs. Mechanistically, CDK4/6i both rapidly accelerates the displacement of MEIS2 from CRBN by IMiD and destabilizes the MEIS2 protein while increasing the CRBN protein in cooperation with IMiD and CELMoD. This enhances CRL4CRBN ubiquitination of IKZF3 and IKZF1 for degradation that exacerbates the loss of IRF4 to relieve IRF7 for induction of the interferon response, culminating in TRAIL-mediated apoptosis. Additionally, MEIS2 promotes BCMA expression and antagonizes repression of BCMA by IMiD and CELMoD for survival of myeloma cells. Thus, CDK4/6i reverses MEIS2 inhibition of CRL4CRBN in cooperation with IMiD and CELMoD, and mitigates MEIS2-mediated BCMA signaling for survival, suggesting targeting MEIS2 and CDK4/6 as a new strategy to advance immunomodulatory drug therapy in multiple myeloma.

cancer biology↗

bioRxiv2025

Integrative machine learning predicts activating kinase mutations for precision oncology

Kinases are enzymes that catalyze phosphorylation and play crucial roles in a myriad of cellular regulatory processes and hemostasis. Patient-specific genetic mutations that aberrantly activate kinases can profoundly influence cancer progression and alter drug efficacy. Predicting the impact of such missense mutations across the human kinome on protein function and cellular signaling is therefore a critical step toward personalized targeted therapy. Here, we present Kinome-AI, an integrative machine learning framework that classifies kinase missense mutations as activating or non-activating. Kinome-AI is trained on a rich multi-modal feature set, including residue-level biochemical changes, sequence embeddings from a protein language model, and structural descriptors of kinase-ATP-substrate complexes derived from molecular modeling. Notably, detailed structural features were available for only 21% of mutants; we leverage these as privileged information during training to impute missing structural data for the remaining [~]79. This strategy boosts performance without requiring structural inputs for new (unseen) mutations. The resulting classifier achieves an area under the receiver operating characteristic curve (AUROC) of 0.85 and a balanced accuracy (BACC) of 0.76 across 1,003 mutations spanning 110 different kinases --substantially outperforming existing bioinformatics and general-purpose variant effect predictors. This work provides a robust approach to quantify sequence-structure- function relationships of cancer-driving kinase mutations, paving the way for improved personalized cancer treatment. Significance StatementIn cancer patients, numerous mutations in diverse protein kinases lead to marked differences in disease progression and drug response. Identifying which kinase mutations are activating in individual patients is therefore critical for precision oncology. Drawing inspiration from teacher- student (privileged information) learning, we developed a deep learning framework that integrates structural features from molecular simulations with sequence embeddings from protein language models. This approach enables accurate binary classification of the activation status of kinase mutations. Our study demonstrates how data-driven algorithms can leverage accumulated sequence and structural knowledge of known mutations to predict the effects of novel variants a priori. The model, termed Kinome-AI, shows significant promise for incorporation into personalized cancer therapy decision pipelines.

cancer biology↗

bioRxiv2025

scRetinaDB: A Comprehensive Database of Single-Cell and Spatial Omics from Cross-Species Retinas

The retina is essential for encoding visual signals, and its dysregulation can lead to retinal diseases. Recent advances in single-cell and spatial sequencing technologies have yielded extensive omics data from retinal tissues across species and biological conditions. However, existing retinal omics data are dispersed across various repositories without uniform processing, which limits integrative analysis. To address this we developed scRetinaDB (https://casapp.dnayun.com/scretina/), a comprehensive resource that aggregates single-cell RNA sequencing (scRNA-seq), single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq), and spatial RNA sequencing (spRNA-seq) data from retinas across species and diverse biological conditions. The database comprises over 2.79 million retinal cells collected from 453 scRNA-seq datasets spanning 34 studies, 17 species and 27 biological conditions. For each species, these scRNA-seq datasets were integrated to construct a retinal cell atlas. In addition, scRetinaDB also contains 107 scATAC-seq and 18 spRNA-seq datasets from human and mouse retinas. The scRetinaDB website provides four major modules separately for browsing species-specific omics data, searching cross-species omics profiles, performing analyses of cell type annotation and cell similarity analysis, and downloading preprocessed multi-omics datasets. Overall, scRetinaDB is a valuable resource for retinal single-cell and spatial omics, advancing cross-species studies particularly in vision research.

bioinformatics↗

bioRxiv2025

Geometric Tuning of Cytokine Receptor Association Modulates Synthetic Agonist Signaling

Cytokines signal by bringing receptor subunits together, but the role of receptor geometry in shaping signaling remains unclear because natural ligands enforce fixed assemblies. Here, we present a de novo protein design platform that rigidly scaffolds receptor-binding domains into defined spatial arrangements. Applying this across IL-7, type I and III interferons, IL-10, gp130, {beta} common, and synthetic receptor pairs, we show that by varying geometry, we can bias pSTAT pathway usage and tune functional outcomes. Geometric control allowed us to decouple pSTAT1 from pSTAT5 in IL-7, separate antigen presentation (MHC-I) from checkpoint induction (PD-L1) in type I interferons, and suppress pro-inflammatory IFN{gamma} secretion while retaining anti-inflammatory activity in IL-10. We further created minimal IL-6 and IL-3 agonists and strengthened synthetic receptor pairings inaccessible with present cytokines. These results establish receptor geometry as a central determinant of cytokine activity and provide a platform for programmable immune modulation.

synthetic biology↗

bioRxiv2025

Implantable Living Materials Autonomously Deliver Therapeutics from Contained Engineered Bacteria

Microbes are increasingly utilized as living therapeutic vehicles, yet their uncontrolled dissemination in the body has long remained a roadblock to clinical development. Physical containment, while widely used for mammalian cells, remains largely unattainable due to eventual bacteria escape. Here, we present an implantable material platform that encapsulates and confines bacteria, wherein synthetically engineered microbes produce therapeutic payloads from within. To prevent microbial escape, we developed a hydrogel scaffold with dual mechanical features: high stiffness to regulate bacterial proliferation and high toughness to resist material fracture under physiological stress. This design achieved complete bacterial containment for over six months and withstood multiple forms of mechanical loading that otherwise caused catastrophic material failure. By genetically engineering embedded bacteria, we endowed the material with environmental sensing and on-demand therapeutic release capabilities and demonstrated autonomous treatment in a murine prosthetic joint infection model. This multimodal strategy provides a safe and generalizable framework for deploying microbial medicines in vivo and supports their use as autonomous drug depots across a range of disease settings.

bioengineering↗

bioRxiv2025

An antifungal with a novel mechanism of action discovered via resistance gene-guided genome mining

Invasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised individuals. Despite this, antifungal drug development has stagnated, with few novel agents and fewer novel targets explored in recent decades. Here, we validate acetolactate synthase (ALS), an enzyme critical for branched-chain amino acid biosynthesis and absent in humans, as a promising target for new therapeutics. Using resistance gene-guided genome mining, we discovered a biosynthetic gene cluster in Aspergillus terreus encoding HB-35018 (1), a novel spiro-cis-decalin tetramic acid that potently inhibits ALS. Biochemical and antifungal assays demonstrate that 1 surpasses existing ALS inhibitors in efficacy against Aspergillus fumigatus and other pathogenic fungi. Structural studies via cryo-electron microscopy reveal a unique covalent binding interaction between compound 1 and ALS, distinct from known inhibitors and finally, we demonstrate that ALS is essential for the virulence in a mouse model of invasive aspergillosis. These findings position ALS as a promising target for antifungal development and demonstrate the potential of resistance gene-guided genome mining for antifungal discovery.

bioengineering↗

bioRxiv2025

Multi-platform framework for mapping somatic retrotransposition in human tissues

Mobile element insertions (MEI) shape the human genome in both germline and somatic tissues. While inherited MEIs are well characterized, mapping somatic MEIs (sMEI) in non-cancer tissues remains challenging due to their low allelic fraction and repetitive nature. We established an integrative framework for sMEI analysis leveraging modern sequencing technologies and analytical innovations. We first benchmarked sMEI detection and demonstrated advantages of long-read and MEI-targeted sequencing for ultra-low-frequency events using a mixture of well-established cell lines. We then showed that haplotype phasing and donor-specific assemblies refine sMEI detection, effectively distinguishing from germline and false signals in in-silico tumor-normal mixtures. We further developed a source-tracing strategy based on internal sequence variation, expanding the catalogue of active source elements beyond traditional transduction-based methods. Applying this framework to donor tissues, we identified 18 rare somatic L1 insertions, revealing structural and source diversity. Our work provides a foundational framework and biological insight into sMEIs.

genomics↗

bioRxiv2025

Vegetation clump size and number as indicators for alternative stable states in semi-arid ecosystems

Dryland ecosystems are vulnerable to desertification, a pressing issue in the face of global climate change. In these ecosystems, vegetation often grows in spatially periodic patterns that differ as aridity increases (gaps, labyrinths and clumps), which has been widely studied theoretically, aiming to assess the proximity of the system to desertification. While some theoretical models predict smooth desertification transitions, most typically predict an abrupt transition linked to the possibility of two alternative stable states (desert and vegetated states), predictions that are yet to be confirmed empirically. If this bistability of alternative stable states occurs, however, environmental fluctuations and the history of the ecosystem determine which state ultimately materializes. This uncertainty makes it harder to predict desertification, compounding the challenges posed by it. Here, we combine empirical data and theoretical methods to investigate the links between bistability and vegetation spatial organization, which can help identify the presence of alternative stable states. We found that, although the presence of vegetation clumps is not indicative of bistability, changes in clump morphology can provide reliable indicators of bistability and an impending desertification transition. Thus, our methodology indirectly identifies whether desertification will occur abruptly, and whether restoration efforts should consider a potential ecosystem history-dependence.

ecology↗

bioRxiv2025

GlialCAM Cytoplasmic Signaling in Oligodendrocytes and Astrocytes is Essential for White Matter Homeostasis in the Brain

Glial cell adhesion molecule (GlialCAM) is an astrocyte- and oligodendrocyte-expressed transmembrane protein with two extracellular IgG-like domains and a cytoplasmic tail with putative signaling functions. While numerous studies have explored functions for the GlialCAM IgG-like domains in brain development and physiology, functions for its cytoplasmic signaling tail remain largely unknown. Therefore, we developed a mutant mouse model that expresses a truncated GlialCAM construct (GlialCAM {Delta}CT) that contains intact extracellular and transmembrane domains but lacks the cytoplasmic tail. Deletion of the GlialCAM cytoplasmic domain in glial cells of the brain results in vacuolization within white matter regions without disrupting neurovascular barrier integrity. Consequently, mutant mice exhibited selective deficits in motor coordination, muscular strength, and memory. Single cell transcriptome sequencing identifies GlialCAM-dependent defects in ECM remodeling pathways in white matter tracts. In situ spatial profiling revealed robust activation of astrocytes and microglia in the mutant brain. Proteomic analysis identified GlialCAM cytoplasmic tail interactors with links to MAPK signaling and cytoskeletal regulatory networks. These data reveal important functions for the GlialCAM cytoplasmic tail in homeostasis of white matter tracts in the adult murine brain. The GlialCAM {Delta}CT model may also be useful for studying the pathogenesis and possible treatment of neurological diseases linked to white matter degeneration.

neuroscience↗

bioRxiv2025

A comprehensive functional landscape of α-tubulin TUBA1A variants illuminates microtubule biology and refines clinical classification

Missense variant interpretation in highly conserved, paralog-rich gene families remains a critical bottleneck for precision medicine. Here, we developed an integrated experimental-computational platform to systematically assess the functional impact of all possible missense mutations in the -tubulin TUBA1A. Combining high-throughput comprehensive mutagenesis, high-content imaging, convolutional neural network- driven phenotyping, and machine learning-guided prediction, we quantified microtubule assembly phenotypes for every coding variant. This approach outperforms conservation-based predictors and enables functional reinterpretation of disease-associated variants. Structural mapping of the TUBA1A mutational landscape reveals distinct domains critical for GTP binding, chaperone-assisted folding or protofilament interaction, illuminating diverse mechanisms of tubulin-related diseases. Integration with ACMG-AMP guidelines demonstrates this mutational landscape improves clinical variant classification in redundant gene families. This framework is broadly applicable to other structurally conserved proteins, linking variant effect prediction to mechanistic insight and clinical translation.

genetics↗

bioRxiv2025

Self-Propelling Adaptive Robotic Microcatheters Enabled by Scalable Fabrication for Intracorporeal Navigation

Minimally invasive therapies demand precise navigation through complex and delicate anatomical pathways, requiring medical tools that are small, flexible, and highly maneuverable. Here, we present a scalable fabrication platform for magnetic tubular microrobots, tethered and untethered, with programmable magnetization, enabling self-propulsion, and an adaptive remote control for targeted interventions. The platform uses Joule heating through a template wire for rapid, and reliable fabrication of microrobots with tunable dimensions. We demonstrate three device configurations: (1) a steerable guiding microcatheter with stiffness modulation; (2) an untethered tubular microrobot (TubeBot) exhibiting wave-crawling locomotion; and (3) a hybrid microcatheter robot that integrates distal-end wave-crawling propulsion with linear insertion to minimize tissue trauma. Validation in tortuous channels, soft phantoms replicating tissue compliance, 3D-printed organ models, ex vivo tissues, and live mice demonstrates the platforms ability to achieve precise microrobotic navigation. The successful targeted delivery of sperm cells, embryos, and drug-mimicking compounds further highlights its potential for precision medicine, including applications in assisted reproduction and targeted drug delivery.

bioengineering↗

bioRxiv2025

Magnetically Controlled Microrobots for In Vivo Non-Invasive Embryo Transfer

Infertility affects millions worldwide and is often linked to factors such as poor sperm quality and female reproductive organ disorders. Despite significant advancements in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), implantation rates remain low, ranging from 17 to 21% after three days of incubation, mainly due to stress, lifestyle factors, and uterine conditions. Extended embryo culture techniques have shown promise in improving pregnancy rates. However, the availability of high-quality blastocysts remains a major challenge. Intrafallopian transfer techniques, such as gamete/zygote intrafallopian transfer (GIFT/ZIFT), were introduced to improve fertilization and early embryo development, particularly for patients with repeated embryo implantation failure (10-30% of assisted reproduction technology (ART) cases, particularly in women >35). However, these methods have declined due to advancements in IVF and the variability in laparoscopy procedures used for GIFT/ZIFT. To address these challenges, we propose a non-invasive microrobotic embryo transfer ({micro}ET) technique using remotely controlled microcarriers comparable in size to embryos. We demonstrate the capabilities of magnetically actuated spiral microrobots, fabricated using laser direct writing for capturing, transporting, and releasing embryos into murine uteri. Additionally, we characterize their motion performance and implement image-guided closed-loop control and dual ultrasound (US)/photoacoustic (PA) tracking for deep-tissue interventions. Recognizing the importance of clinical translation, we present preliminary studies on gelatin-based microrobots, a biodegradable alternative, and explore endometrial remodeling after the in vivo transfer of microrobots carrying embryo-like structures. Our findings show that these microrobots can effectively transport embryos, support their development, and enable minimally invasive delivery, providing a more natural, targeted, and non-invasive strategy for in vivo assisted reproduction. One-Sentence SummaryWe propose a non-invasive {micro}ET technique using magnetically actuated microcarriers to improve embryo cargo-delivery in assisted reproduction, addressing challenges in infertility treatments by enabling precise, image-guided embryo delivery with minimal invasiveness.

bioengineering↗

bioRxiv2025

Programmable Aptamer-Embedded Circular RNAs for Targeted Antigen-Presenting Cells Immunotherapy

The targeted delivery of mRNA to specific cell types in vivo remains a major unmet need in mRNA-based therapeutics. Conventional strategies rely on nanocarriers engineered with various modifications. However, these exogenous materials could cause adverse reactions, and their complex manufacturing processes often hinder clinical application. By leveraging the innate programmability of RNA sequences, we herein report a carrier-free, scalable, and programmable aptamer-embedded circular RNAs (Apt-circRNAs) design that confers targeting capability through the strategic incorporation of different aptamers at varying densities, while retaining circular RNA stability and protein production capability. Experimental results show that antigen-loaded Apt-circRNAs enable targeted delivery to antigen-presenting cells (APCs), drive endogenous antigen expression, activate antigen-specific T cells, and elicit potent immune responses that mediate clearance of both early-and late-stage tumors in mouse models. In humanized models of colorectal cancer, the combination of Apt-circRNA and PD-1 blockade produced synergistic antitumor effects and significantly reshaped the tumor microenvironment. In a first-in-human (FIH) clinical trial, Apt-circRNA vaccine encoding KRAS G12D/G12V neoantigens exhibited a favorable safety profile and induced robust immune activation, T cell mobilization, and neoantigen-specific immune responses. With this study, we have established a new paradigm in carrier-free, APC-targeted RNA vaccine design, offering a safe and effective platform for next-generation cancer immunotherapy.

bioengineering↗

bioRxiv2025

Lzp Ablation Ameliorates Dyslipidemia and Suppresses Atherosclerosis by Reducing Circulating Apolipoprotein B-Containing Lipoproteins

As the principal regulator of systemic lipid homeostasis, the liver uniquely orchestrates dietary lipid assimilation, de novo lipogenesis, very-low-density lipoprotein (VLDL) assembly and secretion, and clearance of atherogenic lipoprotein remnants. This central role positions liver-specific molecular targets as critical therapeutic nodes for mitigating hyperlipidemia and halting atherosclerosis progression. The liver-specific protein Lzp (also named as OIT3), previously shown to stabilize apolipoprotein B (ApoB), the core structural component of triglyceride-rich lipoproteins, has an undefined role in vascular disease pathogenesis. Here, utilizing ApoE-/-mice, a well-established model that closely mimics human atherosclerosis, we demonstrate that Lzp deletion reduces plasma cholesterol, triglycerides, and ApoB levels under both chow and Western diets, concomitant with a marked attenuation of aortic plaque burden. Additionally, Lzp deficiency reduces hepatic and circulating ApoB levels in hyperlipidemic ApoE-/- mice, without exacerbating hepatic steatosis or injury. Mechanistically, Lzp ablation is anticipated to impair hepatic VLDL-ApoB secretion based on our previous findings, resulting in reduced circulating VLDL, intermediate density lipoprotein (IDL) and low-density lipoprotein (LDL) particles, attenuated lipid deposition, and suppressed macrophage-driven plaque inflammation. These results underscore the role of Lzp as a key regulator of systemic lipid metabolism and identify it as a potential candidate for further investigation toward therapeutic intervention of atherosclerotic cardiovascular disease. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/678175v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@118ead8org.highwire.dtl.DTLVardef@e215baorg.highwire.dtl.DTLVardef@1007212org.highwire.dtl.DTLVardef@412757_HPS_FORMAT_FIGEXP M_FIG C_FIG HightlightsO_LILzp deficiency attenuates atherosclerosis and improves plasma lipid profiles in ApoE-/- mice fed chow or Western diets. C_LIO_LILzp deficiency reduces hepatic and circulating apolipoprotein B levels in hyperlipidemic ApoE-/- mice without exacerbating hepatic steatosis or injury. C_LIO_LILzp represents a candidate therapeutic target, warranting further mechanistic and translational studies for atherosclerosis. C_LI

pathology↗

bioRxiv2025

Bayesian inference of lineage trees by joint analysis of single-cell multimodal lineage-tracing data with BiLinT

The advent of single-cell lineage-tracing technologies has enabled simultaneous measurement of gene expression and lineage barcodes. However, integrating these modalities for high-resolution lineage reconstruction has remained challenging due to limitations of methods that analyze modalities separately. In response, we present BiLinT, a Bayesian framework for reconstructing high-resolution cell lineage trees by jointly modeling single-cell multimodal lineage-tracing data. BiLinT integrates lineage barcode evolution (modeled via a continuous-time Markov chain) and gene expression dynamics (modeled via an Ornstein-Uhlenbeck process) within a unified probabilistic model. Applications to synthetic and real datasets demonstrate improved accuracy and reveal developmental fate biases.

bioinformatics↗

bioRxiv2025

A Novel Zebrafish Luminescent Biosensor for Kidney Tubulopathy, Metal Toxicity, and Drug Screening

An efficient endo-lysosomal pathway is crucial to mediate the reabsorption and processing of ultrafiltered solutes including low-molecular-weight (LMW) proteins by the epithelial cells lining the proximal tubule (PT) of the kidney. The zebrafish pronephros is increasingly used as a model system for congenital or acquired disorders that impair the endocytic uptake in PT cells, that cause an inappropriate loss of solutes and LMW proteins in the urine. Here, we describe a new reporter zebrafish line, termed[1/2] vdbp-NanoLuc, in which the vitamin D-binding protein is coupled to NanoLuc luciferase, for rapid, large-scale detection of PT dysfunction and LMW proteinuria. We demonstrate the reliability and value of the[1/2] vdbp-NanoLuc biosensor in fish models of monogenic endolysosomal diseases, gentamicin and cisplatin-induced nephrotoxicity, and metal contamination. This novel system provides mechanistic insights into the cadmium- and copper-induced PT dysfunction and, when combined with a swimming test, a platform for drug screening to alleviate cisplatin toxicity.

pharmacology and toxicology↗