Biology subjects

Tao, L.

Publications and source records attributed to Tao, L..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

SpatialAgent: An Autonomous AI Agent for Spatial Biology

Advances in AI are transforming scientific discovery, yet spatial biology, a field that deciphers the molecular organization within tissues, remains constrained by labor-intensive workflows. Here, we present SpatialAgent, an autonomous AI agent for spatial biology research. SpatialAgent couples large language models with a Plan-Act-Conclude architecture, dynamic tool and skill retrieval, multimodal interpretation, and verification modules that audit generated claims. It supports the full discovery loop, from gene-panel design and multimodal annotation to trajectory inference, cell-cell communication analysis, imputation, and hypothesis generation. Across human and mouse brain, heart, tonsil, colon, and prostate datasets, SpatialAgent outperformed established computational baselines and matched or surpassed expert scientists in key tasks. In open-ended case studies, it recovered known tissue organization and generated spatially grounded hypotheses. In a prospective mouse prostate cancer Xenium study, it designed a compact 100-gene add-on panel that profiled 4.2 million cells across 21 samples, improved cell-type and malignant-state prediction, and captured spatially structured tumor and microenvironment programs. SpatialAgent establishes a framework for autonomous and collaborative discovery in spatial biology.

bioinformatics↗

bioRxiv2025

Characterizing the Microbiome of 'Sterile' Organs in Experimental Mice

Recent studies have shown that microorganisms can be present in organs or blood traditionally considered sterile, both in healthy and diseased individuals. In this study, we investigated the presence of microorganisms in the "sterile" organs (brain, heart, kidney, liver, lung, and spleen) of commercially available experimental mice using culturomics and metagenomics. To avoid potential environmental contamination, strict disinfection assays were performed. Among 104 mice of the C57BL/6J, BALB/c, and ICR strains purchased from three major experimental animal suppliers in China, 23 mice (22.1%) exhibited a high microbial burden (>1 x 104 CFU/g tissue) in at least one organ, and 42 mice (40.4%) exhibited >1 x 103 CFU/g tissue in at least one organ. In total, 216 microbial species were identified through culturomics. Of them, 56 microbial species were found in the organs of at least three mice of the 42 mice (>1 x 103 CFU/g tissue in at least one organ). Metagenomics analysis of 10 high-burden mice verified the existence of microbes in the mouse organs and identified 262 species. Several species, including Acinetobacter sp., Alcaligenes faecalis, and Ligilactobacillus murinus, were identified as the most abundant microbes across both culturomics and metagenomics assays. 16S FISH staining assays verify the presence of microbes in the mouse organs. Feces Metagenomics analysis and detection of the wide distribution of L. murinus in the mouse mesenteric lymph nodes (MLNs) imply that microbial cells could be translocated from the gut to the MLNs and then to the remote tissues. Together, these findings reveal the presence of non-pathogenic microorganisms in the "sterile" tissues of experimental mice, raising concerns about potential variability in experimental outcomes when using such animals in research.

microbiology↗

bioRxiv2025

A study of different pre-treatment methods for cigarettes and their aroma differences

The study innovatively utilized a combination of smoking machine and Cambridge filter to effectively extract the aroma compounds generated during smoking of cigarettes, and employed three different pretreatment methods to obtain optimal cigarette pretreatment procedures. In addition, the aroma components of different cigarettes were identified by different instruments such as gas chromatography-mass spectrometry. Combined with the calculation of Odor Activity Values (OAV), PCA analysis and sensory evaluation were performed on the five types of cigarettes to reveal differences and similarities in their aroma profiles.

biochemistry↗

bioRxiv2025

Pangenome analyses of tea plant reveal structural variations driven gene expression alterations and agronomic trait diversification

Tea plants, one of the worlds most economically significant beverage crops, exhibit extensive genetic diversity and a rich array of secondary metabolites. While structural variations (SVs) are key drivers of phenotypic innovation, their regulatory roles in transcriptional networks and agronomic trait diversification remain underexplored in this perennial crop. We constructed a pangenome from 21 representative tea accessions and their wild relatives. Comparative analysis revealed that wild relatives harbor a greater abundance of gibberellin-related genes, whereas cultivated accessions exhibit an expansion of defense-related genes. We identified 522,428 non-redundant SVs, primarily insertions/deletions (73.56%), which were enriched in promoter regions. These SVs influenced the expression of genes governing flavor compounds, including those involved in flavonoid, amino acid, and terpenoid biosynthesis. Population SV analysis of 275 tea accessions uncovered three haplotypes in the ANS3 gene promoter region, with Hap1, containing a 192 bp insertion, predominantly found in wild relatives but largely lost in modern cultivars. This insertion enhanced CtANS3 expression, increasing anthocyanin accumulation. Additionally, a 159 bp insertion in the CtLRR1 promoter reduced resistance to Colletotrichum gloeosporioides in wild relatives. Our findings underscore SVs as pivotal regulators of genomic diversity, flavor differentiation, and adaptive evolution in tea plant domestication.

genomics↗

bioRxiv2025

SARS-CoV-2 Exploits Host Translation and Immune Evasion Pathways via Viral RNA-Host Protein Interactions

RNA viruses, including SARS-CoV-2, Influenza A Virus (IAV), Zika Virus, and Dengue Virus (DENV) pose serious global health challenges by manipulating host cellular mechanisms. SARS-COV-2, in particular exploits host translational machinery to enhance replication and evade immune response. Here, we investigated how SARS-CoV-2 circumvents host immune defenses through RNA - host protein interactions. By integrating multiple datasets, ClusterProfiler, KEGG, Reactome, WikiPathways, and Gene Ontology, we performed functional enrichment analyses on host protein interactions with SARS-CoV-2 RNA. Our results identified key pathways involved in viral replication, translation regulation, and immune evasion. Comparing SARS-CoV-2 interactomes from IAV, Zika, and DENV, we uncovered a subset of 275 common host proteins serving as promising targets for broad-spectrum antiviral strategies. Network analysis highlighted critical translation factors (EEF1A1, EIF4A1, EIF3H) and RNA-binding proteins (NCL, ILF3) as key nodes in viral replication. These findings provide insights into RNA virus pathogenesis and support the development of targeted therapeutics.

immunology↗

bioRxiv2025

Inducible, virus-free direct lineage reprogramming enhances scalable generation of human inner ear hair cell-like cells

Mammalian inner ear sensory hair cells are highly sensitive to environmental stress and do not regenerate, making hearing loss progressive and permanent. The paucity and extreme inaccessibility of these cells hinder the development of regenerative and otoprotective strategies, Direct lineage reprogramming to generate large quantities of hair cell-like cells in vitro offers a promising approach to overcome these experimental bottlenecks. Previously, we identified four transcription factors--Six1, Atoh1, Pou4f3, and Gfi1 (SAPG)--capable of converting mouse embryonic fibroblasts, adult tail tip fibroblasts, and postnatal mouse supporting cells into induced hair cell-like cells through retroviral or lentiviral transduction (Menendez et al., 2020). Here, we developed a virus-free, inducible system using a stable human induced pluripotent stem (iPS) cell line carrying doxycycline-inducible SAPG. Our inducible system significantly increases reprogramming efficiency compared to retroviral methods, achieving a [~]19-fold greater conversion to a hair cell fate in half the time. Immunostaining, Western blot, and single-nucleus RNA-seq analyses confirm the expression of hair cell-specific markers and activation of hair cell gene networks in reprogrammed cells. The reprogrammed hair cells closely resemble developing fetal hair cells, as evidenced by comparison with a human fetal inner ear dataset. Electrophysiological analysis reveals that the induced hair cell-like cells exhibit diverse voltage-dependent ion currents, including robust, quick-activating, slowly inactivating currents characteristic of primary hair cells. This virus-free approach improves scalability, reproducibility, and the modeling of hair cell differentiation, offering significant potential for hair cell regenerative strategies and preclinical drug discovery targeting ototoxicity and otoprotection.

developmental biology↗

bioRxiv2025

Molecular basis of vitamin K-dependent protein γ-glutamyl carboxylation

Gamma-glutamyl carboxylase (GGCX) in human is the sole enzyme responsible for catalyzing the carboxylation of glutamate (Glu) to {gamma}-carboxyglutamate (Gla), a process that relies on the deprotonation of reduced vitamin K. This post-translational modification of vitamin K-dependent proteins (VKDPs) plays a pivotal role in numerous biological processes. Mutations in GGCX are responsible for multiple clinical phenotypes; however, the molecular mechanisms of GGCX activity and its pathology remain poorly understood. In this study, we reported the cryo-electron microscopy (cryo-EM) structures of GGCX bound with the either FIX or FX, two VKDPs and vitamin K, and employed the biochemical and cellular assays as well as molecular dynamics simulations to elucidate its dual-catalytic properties. The enzyme comprises a transmembrane domain that anchors the vitamin K-binding site, along with an ER luminal domain that facilitates binding of coagulation factor IX (FIX) at the exosite. The catalytic center orchestrates the oxidation of vitamin K and the carboxylation of Glu residues through a Cap-H2 coupling mechanism, along where disease-associated mutations in GGCX are predominantly clustered. These findings offer a comprehensive molecular framework for understanding the allosteric regulation of GGCXs dual enzymatic activities and provide valuable insights for developing strategies to monitor and therapeutically target vitamin K metabolism in related diseases.

biochemistry↗

bioRxiv2025

Single-cell Transcriptomics Unravel Stereocilia Degeneration as a Key Contributor to Age-related Vestibular Dysfunction in Mice and Humans

Age-related vestibular dysfunction (ARVD) is a prevalent, debilitating condition in the elderly. The etiology and molecular mechanisms are poorly understood. We focused on mechanosensitive hair cells (HCs) as they are vulnerable to aging. Using single-cell RNA-seq transcriptomes of young and old mouse vestibular HCs, we show that aging vestibular HCs display both universal molecular signatures, such as genomic instability, mitochondrial dysfunction, and impaired proteostasis, and cell type-specific changes associated with deterioration of hair bundles and mechanotransduction. In alignment with transcriptomic findings, imaging and electrophysiological recordings from aged vestibular sensory epithelia confirmed the degeneration of the hair bundles and a reduction in mechanotransduction. Importantly, this deterioration of hair bundles and vestibular function precedes HC loss, highlighting impaired mechanotransduction as a key contributor to ARVD. Furthermore, molecular and cellular changes associated with aging signatures are less pronounced in vestibular HCs than in cochlear HCs, underscoring tissue-specific age-related differences between the two sensory epithelia in the inner ear.

neuroscience↗

bioRxiv2024

Dual-timescale motor circuit dynamics underlies fast head exploratory behavior and efficient locomotion

Motor systems must balance flexibility and structure to enable efficient and adaptive movements. Traditional hierarchical descending models struggle to explain the intrinsic dynamism in natural behaviors. Here, we investigate the head exploratory behavior of Caenorhabditis elegans, a minimal system capable of intricate motor patterns. Using variational mode decomposition, we identified two distinct motor dynamics: slow rhythmic bends propagating along the body and fast, phase-specific head casts influencing directional bias. Combinatorial ablations of three types of cholinergic motor neurons, in conjunction with dynamical systems analysis, revealed their distinct and overlapping roles: RMD contributes to head casts, SMD sustains bending states, SMB and SMD enable slow rhythmic bending and head-body coupling. Collectively, these neurons form a central pattern generator (CPG) driving forward locomotion. In addition, RMD subgroups displayed unique calcium dynamics correlated with rapid head movements and slow transitions between behavior states. We propose that dual-proprioceptive feedback underlies these multi-timescale dynamics, with slow feedback coordinating rhythmic bending and fast feedback shaping head casts, thereby optimizing roaming efficiency. These findings highlight how intrinsic dynamics and structured composition emerge from highly interactive low-level circuits.

neuroscience↗

bioRxiv2024

Spatially mismatched cerebral blood flow and neuronal activity by intracortical microstimulation

Intracortial microstimulation (ICMS) is widely used in brain-machine interface for neuroprosthetics, particularly with aims of restoring lost sensory and motor functions. However, it remains poorly understood whether neuronal and blood flow responses by ICMS are spatially and temporally matched, as well as their underlying mechanism. Neurovascular coupling (NVC) is the process by which neuronal activity regulates blood flow in the brain to meet local metabolic demands. A hypothetically suboptimal NVC by ICMS may exacerbate the neuronal survival near electrode, contributing to neurodegeneration. In this study, we used wide-field imaging, laser speckle imaging and two-photon imaging in transgenic mice expressing calcium fluorescent indicators in neurons or vascular mural cells to examine this hypothesis. Our results showed blood flow responses are delayed at peak time and prolonged in duration compared with neuronal responses. By varying the stimulation amplitudes, we found that low stimulation intensity lower than 50A preserved NVC. In contrast, high intensity stimulation caused spatially mismatched NVC, i.e. in the adjacent range within 200[~]400 m from electrode tip, elicited blood flow compromises but neuronal activities increase. Ca2+ is the key regulator of contractile tone of vascular mural cells. Our results showed that Ca2+ sensitivity at vascular mural cells, i.e. vessel diameter change per unit of Ca2+ change, was decreased in the adjacent region of electrode, which partially explained the compromised and mismatched NVC, and which likely further lead to ischemia and neurodegeneration. This study offers a new insight into ICMS-associated neuronal and vascular physiology, and provides an important implication towards optimal design of ICMS: low intensities is more neuroprotective than high intensities by preserving NVC and preventing ischemia. Our discoveries pave the way for new research consideration and contribute to the development of more advanced brain-machine interface.

neuroscience↗

bioRxiv2024

METTL3 inhibition-activated cGAS/STING axis enhances immunotherapy and PARP inhibitor sensitivity of lung carcinoma

The cGAS/STING-mediated type I interferon response can augment antitumor activity, while the regulatory factors within this innate immune response remain elusive. Herein we found that the RNA m6A methyltransferase METTL3 was upregulated in lung carcinoma tissues. Elevated METTL3 level was correlated with diminished CD8+ T cell infiltration and cancer progression in lung carcinoma patients. METTL3 deficiency exacerbated nuclear DNA leakage into the cytoplasm, activating the cGAS pathway and thereby enhancing anti-tumor immunity. Mechanistically, METTL3 deficiency reduced the homologous recombination repair efficacy via downregulation of MSH5, a mutS family protein involved in DNA mismatch repair, leading to increased cytosolic DNA levels. m6A methylation of A2521 of MSH5 stabilized its mRNA via binding with IGF2BP2. On the other hand, m6A methylation of A1545 at the CDS of cGAS decreased mRNA stability and regulates its protein expression. Functionally, knockdown of METTL3 sensitized lung carcinoma cells to the PARP inhibitors. In vivo and clinical data confirmed the positive roles of METTL3 inhibition-activated cGAS/STING axis in tumor growth and lung adenocarcinoma progression. Collectively, METTL3 inhibition activates the cGAS/STING-mediated anti-tumor immunity via induction of cytosolic DNA and cGAS expression, which in turn regulate PARP inhibitor response and cancer progression in lung carcinoma.

cancer biology↗

bioRxiv2024

The neurovascular coupling response of the aged brain is brain-state dependent.

Brain aging lead to reduced cerebral blood flow and cognitive decline, but how normal aging affects neurovascular coupling (NVC) in the awake brain is unclear. Here, we investigated NVC in relation to calcium changes in vascular mural cells (VMCs) in awake adult and aged mice. We show that NVC responses are reduced and prolonged in the aged brain and that this is more pronounced at the capillary level than in arterioles. However, the overall NVC response, measured as the time integral of vasodilation, is the same in two age groups. In adult, but not in aged mice, the NVC response correlated with Ca2+ signaling in VMCs, while the overall Ca2+ kinetics were slower in aged than in adult mice. In particular, the rate of Ca2+ transport, and the Ca2+ sensitivity of VMCs were reduced in aged mice, explaining the reduced and prolonged vasodilation. Spontaneous locomotion was less frequent and reduced in aged mice as compared to young adult mice, and this was reflected in the slow but prolonged NVC and vascular Ca2+ responses. Taken together, our data characterize the NVC in the aged awake brain as slow but prolonged, and underscoring the importance of brain state in understanding age-related mechanisms.

neuroscience↗

bioRxiv2024

Interspecies interaction reshapes the fitness landscape of evolved genotypes

Microbial interaction and their evolution is vital for shaping the structure and function of microbial communities. However, the mechanisms governing the directionality and stability of the evolution of interactions within microbial communities remain poorly understood. Here, we used a syntrophic two-species biofilm consortium composed of Bacillus velezensis SQR9 and Pseudomonas stutzeri XL272 that promotes plant growth through their metabolic interactions and investigated how the interactions within the consortium change over evolutionary timescale to characterize the phenotypic and genetic diversification. The focal species B. velezensis SQR9 rapidly diversified into diverse colony morphotypes, both in the presence and absence of its interactor, P. stutzeri XL272, with variable frequencies. These morphotypes displayed phenotypic differentiation among biofilm formation, planktonic growth, and spore formation. The evolved P. stutzeri altered the fitness landscape of B. velezensis morphotypes, allowing the weaker rough morphotype to outcompete the biofilm-enhanced slimy morphotype. Whole genome re-sequencing correlated these phenotypic changes with mutations in specific genes encoding regulators of B. velezensis, including ywcC, comA, comP, degS, degQ and spo0F. The coevolutionary partner, P. stutzeri increased its exopolysaccharide production that could be explained by a frame shift mutation in cpsA gene encoding capsular polysaccharide (CPS) biosynthesis protein. Compared with the mono-evolution, co-evolved B. velezensis populations showed greater mutation accumulation in intergenic regions, which led to greater genetic parallelism. Furthermore, the dissimilarity between mono-evolved and co-evolved populations increased over time. Our study reveals intricate genetic diversification and fitness differentiation within a biofilm consortium, shaped by both abiotic conditions and biotic interactions.

microbiology↗

bioRxiv2024

Systematic identification of secondary bile acid production genes in global microbiome

Microbial metabolism of bile acids (BAs) is crucial for maintaining homeostasis in vertebrate hosts and environments. Although certain organisms involved in BA metabolism have been identified, a global, comprehensive elucidation of the microbes, metabolic enzymes, and BA remains incomplete. To bridge this gap, we employed hidden Markov models to systematically search in a large-scale and high-quality search library comprising 28,813 RefSeq multi-kingdom microbial complete genomes, which enabled us to construct a secondary bile acid (SBA)-production gene catalog. This catalog greatly expanded the distribution of SBA-production genes across 11 phyla, encompassing bacteria, archaea and fungi, and extended to 14 habitats spanning hosts and environmental contexts. Furthermore, we highlighted the associations between SBAs and gastrointestinal and hepatic disorders, including inflammatory bowel disease, colorectal cancer and nonalcoholic fatty liver disease, further elucidating disease-specific alterations in SBA-production genes. Additionally, we proposed the pig as a particularly suitable animal model for investigating SBA production in humans, given its closely aligned SBA-production gene composition. This gene catalog provides a comprehensive and reliable foundation on microbial BA metabolism for future studies, offering new insights into the microbial contributions to health and disease.

genomics↗

bioRxiv2024

Bridging the Gap: biofilm-mediated establishment of Bacillus velezensis on Trichoderma guizhouense mycelia

Bacterial-fungal interactions (BFIs) are important in ecosystem dynamics, especially within the soil rhizosphere. The bacterium Bacillus velezensis SQR9 and the fungus Trichoderma guizhouense NJAU 4742 have garnered considerable attention due to their roles in promoting plant growth and protecting their host against pathogens. In this study, we utilized these two model microorganisms to investigate BFI. We firstly demonstrate that while co-inoculation of B. velezensis and T. guizhouense could promote tomato growth, these two microorganisms display mutual antagonism on agar solidified medium. To resolve this contradiction, we developed an inoculation method, that allows B. velezensis colonization of T. guizhouense hyphae and performed a transcriptome analysis. During colonization of the fungal hyphae, B. velezensis SQR9 upregulates expression of biofilm related genes (e.g. eps, tasA, and bslA) that is distinct from free-living cells. This result suggested an intricate association between extracellular matrix expression and hyphae colonization. In accordance, deletion epsD, tasA, or both epsD and tasA genes of B. velezensis diminished colonization of the T. guizhouense hyphae. The insights from our study demonstrate that soil BFIs are more complex than we understood, potentially involving both competition and cooperation. These intricate biofilm-mediated BFI dynamics might contribute to the remarkable diversity observed within soil microbiota, providing a fresh perspective for further exploration of BFIs in the plant rhizosphere.

microbiology↗

bioRxiv2024

The dual resistance mechanism of CYP325G4 and CYP6AA9 in Culex pipiens pallens legs according to transcriptome and proteome analysis

Mosquitoes within the Culex pipiens complex play a crucial role in human disease transmission. Insecticides, especially pyrethroids, are used to control these vectors. Mosquito legs are the main entry point and barrier for insecticides to gain their neuronal targets. However, the resistance mechanism in mosquito legs is unclear. Herein, we employed transcriptomic analyses and isobaric tags for relative and absolute quantitation techniques to investigate the resistance mechanism, focusing on Cx. pipiens legs. We discovered 2346 differentially expressed genes (DEGs) between deltamethrin-resistant (DR) and deltamethrin-sensitive (DS) mosquito legs, including 41 cytochrome P450 genes. In the same comparison, we identified 228 differentially expressed proteins (DEPs), including six cytochrome P450 proteins). Combined transcriptome and proteome analysis revealed only two upregulated P450 genes, CYP325G4 and CYP6AA9. The main clusters of DEGs and DEPs were associated with metabolic processes, such as cytochrome P450-mediated metabolism of drugs and xenobiotics. Transcription analysis revealed high CYP325G4 and CYP6AA9 expression in the DR strain at 72 hours post-eclosion compared with that in the DS strain, particularly in the legs. Mosquitoes knocked down for CYP325G4 were more sensitive to deltamethrin than the controls. CYP325G4 knockdown reduced the expression of several chlorinated hydrocarbon (CHC)-related genes, which altered the cuticle thickness and structure. Conversely, CYP6AA9 knockdown increased CHC gene expression without altering cuticle thickness and structure. P450 activity analysis demonstrated that CYP325G4 and CYP6AA9 contributed to metabolic resistance in the midgut and legs. This study identified CYP325G4 as a novel mosquito deltamethrin resistance factor, being involved in both metabolic and cuticular resistance mechanisms. The previously identified CYP6AA9 was investigated for its involvement in metabolic resistance and potential cuticular resistance in mosquito legs. These findings enhance our comprehension of resistance mechanisms, identifying P450s as promising targets for the future management of mosquito vector resistance, and laying a theoretical groundwork for mosquito resistance management. Author SummaryCulex pipiens mosquitoes are the primary vector of the filamentous nematode, Wuchereria bancrofti and also involved in the transmission of other pathogens, such as West Nile virus (WNV), avian malarias, and avian pox virus. Insecticides, particularly pyrethroids, continue to be the primary method to control these significant vectors. Worryingly, resistance to insecticides has become widespread and is rapidly intensifying in Culex mosquitoes throughout China, posing a threat to the efficacy of insecticides. Legs are the main sites of contact with ITNs and sprayed insecticides, and the insecticides have to penetrate the leg cuticle to reach their targets.Therefore, the resistance mechanisms in mosquito legs deserve further investigation. Several reports have found a certain amount of P450 in insect legs. Unfortunately, none of the above reports have conducted further functional studies on P450s in the legs. Here, we have identified two P450 enzymes, CYP325G4 and CYP6AA9, through the integrated analysis of transcriptomics and proteomics. CYP325G4 enriched in the cuticle of resistant mosquitoes might possess a dual resistance mechanism involving metabolic resistance and cuticle resistance. CYP6AA9 was slightly different, possibly exerting metabolic resistance as its main function and also being involved in cuticle synthesis. Understanding the dual resistance mechanism of P450s in the metabolism of pyrethroid insecticides will have an important role in optimizing vector control strategies.

physiology↗

bioRxiv2024

Stochastic growth and selective stabilization generate stereotyped dendritic arbors

Stereotyped dendritic arbors are shaped by dynamic and stochastic growth during neuronal development. It remains unclear how guidance receptors and ligands coordinate branch dynamic growth, retraction, and stabilization to specify dendritic arbors. We previously showed that extracellular ligand SAX-7/LICAM dictates the shape of the PVD sensory neuron via binding to the dendritic guidance receptor DMA-1, a single transmembrane adhesion molecule. Here, we perform structure-function analyses of DMA-1 and unexpectedly find that robust, stochastic dendritic growth does not require ligand-binding. Instead, ligand-binding inhibits growth, prevents retraction, and specifies arbor shape. Furthermore, we demonstrate that dendritic growth requires a pool of ligand-free DMA-1, which is maintained by receptor endocytosis and reinsertion to the plasma membrane via recycling endosomes. Mutants defective of DMA-1 endocytosis show severely truncated dendritic arbors. We present a model in which ligand-free guidance receptor mediates intrinsic, stochastic dendritic growth, while extracellular ligands instruct dendrite shape by inhibiting growth.

neuroscience↗

bioRxiv2024

Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response

Monounsaturated fatty acids (MUFAs) play a pivotal role in maintaining endoplasmic reticulum (ER) homeostasis, an emerging hallmark of cancer. However, the role of polyunsaturated fatty acid (PUFAs) desaturation in persistent ER stress driven by oncogenic abnormalities remains elusive. Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain PUFAs. Our previous research has demonstrated the significant role of FADS1 in cancer survival, especially in kidney cancers. We explored the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 effectively inhibits renal cancer cell proliferation and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we show that while FADS1 inhibition induces ER stress, its expression is also augmented by ER-stress inducers. Notably, FADS1-inhibition sensitized cellular response to ER stress inducers, providing evidence of FADS1s role in modulating the ER stress response in cancer cells. We show that, while FADS1 inhibition-induced ER stress leads to activation of ATF3, ATF3-knockdown rescues the FADS1 inhibition-induced ER stress and cell growth suppression. In addition, FADS1 inhibition results in the impaired biosynthesis of nucleotides and decreases the level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.

cancer biology↗