Biology subjects

Su, X.

Publications and source records attributed to Su, X..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Serial vaccination expands and refines human CD4+ T cell memory

CD4+ T cells coordinate protective immunity against pathogens. However, a major unresolved question is how human CD4+ T cell memory is established and evolves following primary and repeated vaccination. Using COVID-19 mRNA vaccination as a model, we tracked 50 distinct antigen-specific populations directly ex vivo with peptide-MHC class II tetramers in eight SARS-CoV-2-naive individuals from pre-vaccine baseline through memory time points after three mRNA doses. Our findings identify the primary vaccine series as the main driver of memory pool size. It leverages pre-existing memory while preferentially recruiting high-avidity T cells, establishing an immunodominance hierarchy dominated by a small subset of precursors. Booster vaccination refines both the magnitude and quality of T cell memory. It increases select populations and enhances differentiation of subdominant CD4+ T cells. Populations that did not become more abundant after boosting retained their polyfunctional potential. Beyond establishing memory to the ancestral spike, vaccinations broadened responses by recruiting cross-reactive T cells recognizing viral variants. Collectively, these findings reveal how human CD4+ T cell memory evolves through sequential immunizations to generate a functionally diverse and broadly responsive memory repertoire against future viral challenges.

immunology↗

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

The mechanism of Hsa_circ_0000629 in bronchial asthma through sponge adsorption of miR-212-5p/NLRP3

To explore the mechanism of Hsa_circ_0000629 adsorbing miR-212-5p/ nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) through sponge in bronchial asthma. Twenty BALB/C mice were randomly divided into a normal control group and an asthma group. Pathological changes in lung tissue were observed via HE staining. Human bronchial epithelial cells (16HBE) were transfected with Hsa_circ_0000629 overexpression group (Hsa_circ_0000629-over), Hsa_circ_0000629 siRNA (Hsa_circ_0000629-si), mimic NC, miR-212-5p mimic, inhibitor NC, miR-212-5p inhibitor, and LPS+Hsa_circ_0000629 si. LPS-induced asthmatic cell models (LPS group) and untransfected 16HBE cells (NC group) served as controls. qRT-PCR was used to measure Hsa_circ_0000629, miR-212-5p and NLRP3 expression. ELISA assessed interleukin 18 (IL-18), interleukin 1{beta} (IL-1{beta}), interleukin 6 (IL-6) and tumor necrosis factor - (TNF-) levels. Cell proliferation and the apoptosis were evaluated by EDU assay and flow cytometry, respectively. Western blot analyzed Cleaved-caspase 1, 3 and 9 proteins expression. Dual-luciferase assay verified the binding sites of Hsa_circ_0000629 to miR-212-5p and NLRP3 to miR-212-5p. HE staining revealed inflammatory cell infiltration, bronchial wall thickening, smooth muscle hyperplasia, and alveolar destruction in asthmatic mice. Compared with the controls, Hsa_circ_0000629 and NLRP3 expression were significantly increased, while miR-212-5p expression was decreased in asthmatic lung tissues. In 16HBE cells, Hsa_circ_0000629-over and LPS groups showed elevated Hsa_circ_0000629 and NLRP3 expression but reduced miR-212-5p levels. Silencing Hsa_circ_0000629 in LPS-treated cells (LPS+Hsa_circ_0000629-si) reversed these effects. Overexpression of miR-212-5p counteracted Hsa_circ_0000629-induced NLRP3 upregulation, while miR-212-5p inhibition enhanced NLRP3 expression. LPS exposure increased TNF-, IL-18, IL-6, and IL-1{beta} levels, reduced cell proliferation, and promoted apoptosis. These changes were attenuated by Hsa_circ_0000629 silencing or miR-212-5p overexpression. Western blot confirmed that Hsa_circ_0000629 overexpression upregulated Cleaved-Caspase 1, 3, and 9, whereas miR-212-5p mimic or Hsa_circ_0000629-si reversed this trend. Dual-luciferase assays demonstrated targeted interactions among Hsa_circ_0000629, miR-212-5p, and NLRP3. Interference with Hsa_circ_0000629 expression can alleviate LPS induced apoptosis in 16HBE cells and inhibit the expression of inflammatory factors by targeting the miR-212-5p/NLRP pathway, which may be a new target for the treatment of asthma.

immunology↗

bioRxiv2026

Cell Type Architecture and Positional Gene Gradients in an Adult Animal at Subcellular Resolution

The spatial organization of cell types and gene expression underlies tissue architecture and organismal physiology. However, resolving complete cellular and molecular landscapes within a three-dimensional context remains challenging, particularly in organisms with high cellular heterogeneity and complex geometry. Here, we developed a semi-supervised workflow to reconstruct high-resolution three-dimensional spatial transcriptomic models of the planarian Schmidtea mediterranea at single-cell resolution. Planarians are basal bilaterians capable of regenerating body structures after injury. Our reconstruction maps the distribution of cell types and spatially patterned gene expression across the intact organism and identifies 119 candidate positional control genes (PCGs). These genes are expressed across muscle, neural, and epidermal populations. Functional perturbation of selected candidates, including pitx3, ptpn11, pi4ka, upf3b, and cul1, revealed roles in regeneration following injury. In addition, we identify intestinal cells as prominent components of the microenvironment surrounding adult tgs1 pluripotent stem cells (neoblasts). Together, these results demonstrate the utility of three-dimensional spatial transcriptomic reconstruction for mapping cellular architecture and positional gene regulation in complex adult organisms.

developmental biology↗

bioRxiv2026

4D Single-Cell Spatial Transcriptomics Reveals Dynamic Morphogenetic Gradients and Regenerative Domains in Planarians

Regeneration relies on precise spatiotemporal gene expression and cellular responses to establish tissue identity and body patterning. Using high-resolution Stereo-seq (715 nm) on 353 sections from 16 whole animals at 8 regeneration timepoints, we constructed a 4D spatiotemporal transcriptomic map of planarian regeneration. Our analysis captured 36 refined cell types from 3,508,004 segmented cells, enabling genome-wide transcriptional imputation of gene expression dynamics across body axes at cellular, tissue, and organismal scales. We identified dynamic positional gradients and distinct spatially distributed cell types during regeneration, including an injury-induced Anterior Regenerative Zone (ARZ). The ARZ exhibited enriched positional signals in epidermal, muscle, and neural cells and was regulated by Mediator 8, which is crucial for polarity remodeling and blastema formation. This study provides a comprehensive spatial molecular and cellular map of regenerative processes, highlighting injury-induced spatial domains and key regulatory factors in planarian regeneration. We also provide an interactive web portal, offering a valuable resource for exploring and analyzing regeneration mechanisms in a spatiotemporal context.

developmental biology↗

bioRxiv2026

Multi-omics analysis identifies intrinsic Trp53 driven metastatic breast cancer subtypes.

Metastatic breast cancer (mBC) is deadly, and its molecular drivers are largely unknown. Treatment is limited to systemic cytotoxic chemotherapies and tumors often become refractory. The most frequently mutated gene in MBC is TP53. The TP53R248W hotspot missense mutation is associated with poor prognosis. We generated a somatic mouse model of mammary epithelial specific Trp53R245Wexpression. Primary tumors were highly metastatic, reflecting the human molecular subtypes luminal A, luminal B, HER2, and TNBC. Transcriptomic profiling revealed three intrinsic subtypes: stem-cell like (SCL), well-differentiated metabolically active (WDMA), and immunosuppressed (IS). SCL tumors activate ribosome biosynthesis and E2F signaling, amplifying Met, Birc3, Yap1 and deleting Nf1, Pik3r1, and Rad17. WDMA tumors activate cytochrome P450 enzymes, estrogen signaling and branched chain amino acid degradation, with mutations activating Pi3k/Akt/mTOR signaling. IS tumors activate immune suppression, have high mutation burden, and frequently mutate Traf7 and delete Cdkn2a. This is the most comprehensive transcriptomic and genomic profiling of mutant p53-driven breast tumors, elucidating potential therapeutic targets. TeaserA single Trp53 mutation drives intrinsic metastatic breast cancer subtypes with distinct transcriptomes and genomic alterations.

cancer biology↗

bioRxiv2026

Negative frequency-dependent selection maintains partner quality variation in a keystone nutritional mutualism

Mutualisms, interactions that benefit both partners, are critical for promoting biodiversity and ecosystem resiliency, yet are considered evolutionarily unstable and vulnerable to global change. Understanding how genetic variation in mutualisms is maintained is key to predicting their future persistence and explaining their long evolutionary history. While theory addresses factors maintaining variation in partner quality (the fitness benefits partners provide), few studies have experimentally tested these mechanisms. Here, we experimentally evolved multiple replicate populations of rhizobia, nitrogen-fixing mutualists of legumes, varying in partner quality under contrasting environments: nitrogen (N)-supplemented or N-free conditions, with or without host plants. After one year of rhizobial evolution, we quantified selection on partner quality across environments and evaluated resulting changes in mutualism traits and population-level genetic diversity. Strikingly, selection on partner quality was population-dependent: high-quality strains were favoured when initially rare but disfavoured when common, revealing negative-frequency dependent dynamics that can maintain variation. Although neither nitrogen-supplementation nor host presence directly imposed selection, both were critical for preserving genetic diversity in rhizobia populations - fuel for ongoing evolution. By demonstrating negative-frequency dependent selection in the legume-rhizobium mutualism, our study reveals a dynamic more akin to antagonistic interactions than traditionally assumed. This overlooked mechanism may be the key to explaining the ecological and evolutionary persistence of mutualisms under changing environments. Significance StatementMutualisms are central to biodiversity, yet their stability is puzzling because the mechanisms thought to stabilize them tend to eliminate the genetic variation needed for continued adaptation, even though partners in nature show striking variation in quality. In an experimental evolution study of a keystone plant-microbe mutualism (legume-rhizobium symbiosis), we found that negative frequency-dependent selection allows high- and low-quality symbionts to coexist: high-quality strains are favoured only when rare. Environmental factors such as nitrogen addition or host presence did not alter which partners were selected, but they helped maintain genetic diversity needed for future adaptation. Our findings reveal an overlooked mechanism that stabilizes mutualisms and explain how these interactions can remain resilient under changing environmental conditions.

evolutionary biology↗

bioRxiv2026

Evolutionary genomics of local adaptation, climate vulnerability, and linarin metabolism in Opisthopappus longilobus

Global climate change and human activities are posing substantial threats to biodiversity. The genus Opisthopappus (O. taihangensis and O. longilobus), endemic to Chinas Taihang Mountains, possesses great ecological, ornamental and medicinal value. However, it is confronted with the pressures of habitat fragmentation and climate change. Here, we present the first haplotype-resolved, chromosome-scale genome assembly of O. longilobus ([~]2.95 Gb) and re-sequence 115 individuals across its range. Comparative analyses show Opisthopappus is sister to Artemisia-Chrysanthemum, with Opisthopappus and Chrysanthemum diverging at 5.15-5.18 million years ago. A profound genetic divergence is evident between O. taihangensis and O. longilobus, resulting in two distinct lineages within each species, driven by geography and climate. Our analyses indicate restricted gene flow, low diversity, and recurrent demographic bottlenecks collectively contribute to their endangerment. By integrating population genomics and environmental variables, we identified 4,437 core adaptive genes linked to water deprivation, and metabolism. Genomic offset predicts higher maladaptation risk in populations under drastic climate change. Furthermore, diverged promoters of two O-methyltransferase genes, OMT250 and OMT310, likely underlie the differential acacetin/linarin accumulation between C. morifolium and O. longilobus. These findings advance understanding of Opisthopappus evolution and climate vulnerability, offering a model for genomics-guided biodiversity conservation.

plant biology↗

bioRxiv2025

Mast cell extracellular granules are bioactive condensates driven by heparin and polyamine

Biomolecular condensates are membraneless bodies that organize biochemical reactions typically within cells. However, the roles of condensates in extracellular space--where conditions differ substantially from intracellular space--remain poorly understood. Here, we report mast cell extracellular granules (MCEGs), a stable membraneless entity, are condensates assembled via electrostatic interactions between glycosaminoglycans and polyamines. Disrupting polyamine synthesis or trafficking blocks MCEG formation and compromises the storage of proteases and cytokines. Granules reconstituted with heparin and spermine are sufficient to enrich mediators such as CPA3 and TNF, maintaining an elevated pH and higher concentrations of calcium and zinc compared to the extracellular milieu. This unique environment enhances CPA3 enzymatic activity. Furthermore, the granules increase TNF binding and its bioactivity toward endothelial cells. Together, we reveal MCEGs as functionally active biomolecular condensates with distinct biochemical and immunological properties; MCEGs are formed through sugar-metabolite interactions, expanding the mechanisms of condensate assembly beyond classical protein-protein and protein-RNA interactions.

cell biology↗

bioRxiv2025

PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia

Loss of the tumor suppressor PTEN is common in T-cell acute lymphoblastic leukemia (T-ALL), and is associated with poor prognosis. PTEN-loss drives robust activation of AKT/mTORC1 signaling to promote leukemic cell growth. We find that PTEN-loss in T-ALL confers dependence on the guanylate nucleotide synthesis enzyme inosine 5-monophosphate dehydrogenase (IMPDH) for cell growth and viability. This metabolic vulnerability is dependent on sustained mTORC1 signaling and can be exploited using clinically approved IMPDH inhibitors to selectively kill PTEN-deficient T-ALL cells, and extend survival in genetic and xenograft T-ALL models in mice. Mechanistically, IMPDH inhibitors cause early DNA replication stress, followed by DNA damage. In contrast to treatment with mTORC1 inhibitors, these events culminate in robust and selective cell death in PTEN-deficient T-ALL cells. These findings reveal a targetable metabolic vulnerability in T-ALL, which could provide rationale for repurposing clinically approved IMPDH inhibitors. Statement of SignificanceWe find that the IMPDH inhibitors mycophenolic acid and mizoribine, which are currently used as well-tolerated immunosuppressants, exert anti-leukemic activity in an aggressive molecular subset of T-ALL cells that are associated with poor prognosis. The use of clinically approved compounds to exploit this vulnerability could lead to rapid drug repurposing.

cancer biology↗

bioRxiv2025

A dietary pan-amino acid dropout screen in vivo reveals a critical role for histidine in T-ALL

Dietary interventions show therapeutic potential in cancer, but systematic comparisons are lacking. We performed a dietary pan-amino acid dropout screen in an orthotopic model of NOTCH1-driven T-cell acute lymphoblastic leukemia and identified histidine depletion as uniquely antileukemic. Histidine-restricted diets extended survival of leukemic mice in a dose-dependent manner, while remaining well-tolerated. Mechanistically, multiomic profiling revealed that histidine deprivation-induced ribosome stalling activates GCN2 to suppress cholesterol biosynthesis pathways critical for leukemic proliferation. Dietary cholesterol supplementation partially reverted the antileukemic effects of histidine restriction in vivo. These findings couple histidine levels and translational control to cholesterol metabolism, which can be therapeutically exploited for cancer treatment. Our results suggest that defined dietary amino acid restrictions may expose broader therapeutic opportunities in diseases beyond cancer.

cancer biology↗

bioRxiv2025

TAp73 mediates anti-tumor immunity through regulation of lipid metabolism in the lung tumor microenvironment

While immunotherapy has become the standard of care for lung adenocarcinoma (LUAD) patients without actionable genomic alterations, only a subset of patients benefits from a long-lasting response to immunotherapy. Activation of p53-related signals has emerged as a potential mediator of the lung tumor microenvironment (TME). Given that mutant-p53 interacts with p73 extensively and TAp73-deficient mice develop LUAD, we engineered a mouse model with conditional deletion of TAp73 to understand the interactions of the p53 family in the TME and in metabolic pathways that impact anti-tumor immunity. We demonstrated that TAp73 exerts a tumor-suppressive role in KrasG12D-driven LUAD by regulating lipid metabolism in the TME. We identified a TAp73-driven transcriptional signature involving genes in the arachidonic acid metabolism pathway operational in tumor-associated macrophages that favors T-cell activation and thus anti-tumor immunity. Similar transcriptional changes are seen in macrophages from LUAD patients with p53 mutations and in association with response to immunotherapy. SIGNIFICANCEThere is a need to understand how the LUAD TME impacts patient response to immunotherapy. We identified a transcriptional program enacted by TAp73 in tumor alveolar macrophages that supports T-cell activation. Transcriptional and metabolomic data from LUAD patients supports the relevance of this program in response to immune checkpoint inhibition.

cancer biology↗

bioRxiv2025

Live-Cell Covalent Profiling Reveals Principles of RNA-Small Molecule Recognition across the Human Transcriptome

RNA folds are abundant in mammalian cells yet poorly characterized as small-molecule targets. We present a scalable, unbiased live-cell pipeline that maps where small molecules bind RNA across the human transcriptome and convert those binders into selective degraders. A 200-member fragment library bearing diazirine/alkyne handles yielded 23 RNA-binding candidates. Chem-CLIP-Map-Seq in MDA-MB-231 cells identified 723 RNA targets and their binding sites, revealing a strong bias toward 5' and 3' untranslated regions (UTRs) in mRNAs and enrichment at thermodynamically stable structures, with limited binding to non-coding RNAs. Expression level and local stability contributed to engagement. An integrated machine-learning model trained on multiple fingerprints distinguished binders from non-binders, and highlighted chemotypes and physicochemical features that favor RNA recognition. Four fragments were converted to RiboTACs; despite broad binding, cleavage was highly selective, with X1-RiboTAC degrading MPP7 and SSC4D mRNAs in an RNase L-dependent manner and reducing their protein levels. A competitive profiling workflow quantified in-cell target occupancy and guided optimization of the RNA-binding module to reprogram selectivity: an X1 derivative produced an MPP7-selective RiboTAC that lowered MPP7 mRNA levels and suppressed breast-cancer cell migration, while sparing SSC4D transcripts. This end-to-end framework, including transcriptome-wide mapping, data-driven rules, and tunable degradation, establishes practical principles for ligandable RNA sites in cells and enables rational design of RNA-targeted small molecules and degraders. TEASERLive-cell mapping reveals ligandable RNA sites and guides design of selective RNA degraders. TOC graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/686775v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@a216c8org.highwire.dtl.DTLVardef@185c59eorg.highwire.dtl.DTLVardef@17131e2org.highwire.dtl.DTLVardef@81ffa2_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Human Organoids Reveal PTEN-driven Mesendoderm Specification via Retinoic Acid Signaling Suppression

During early embryogenesis, epiblast cells ingress through the primitive streak (PS) and commit to a mesendoderm (MES) fate, giving rise to both mesodermal and endodermal lineages. Despite advancements in human organoid technology for modeling pre-implantation blastocyst stage, robust systems that accurately recapitulate MES specification and PS formation during the post-implantation stage remain limited. Here, we show that human induced pluripotent stem cells can be used to generate three-dimensional MES organoids that faithfully mimic in vivo human MES specification, particularly from the anterior PS. We demonstrate that MES organoid formation is dependent on PTEN expression and that loss of PTEN severely impairs the formation of mesoderm and definitive endoderm derivatives arising from MES organoids. To elucidate the molecular mechanisms underlying these defects, we conducted an integrative multi-omics analysis, including transcriptome, chromatin accessibility profiling, metabolism, and phosphoproteomics, on wild-type and PTEN-/-MES cells. These analyses revealed that PTEN suppresses retinoic acid (RA) signaling during MES lineage commitment. Furthermore, we identified the RA-degrading enzyme CYP26A1 as a downstream effector of PTEN. Notably, while excessive RA induced by PTEN ablation is detrimental to MES cell generation, physiological levels of RA are necessary. Collectively, our human MES organoids offer a valuable model for dissecting early human development, and our findings identify PTEN as a key regulator of MES fate commitment through inhibition of RA signaling.

developmental biology↗

bioRxiv2025

Coxiella burnetii infects osteoclasts and alters their differentiation and function in a type IV secretion system-dependent manner

1Chronic Q fever is caused by persistent infection with the Gram-negative bacterium Coxiella burnetii. The mechanisms underlying this persistence remain elusive, but the presence of the bacteria in the bone marrow of C. burnetii-infected patients has been demonstrated. Therefore, we investigated the potential role of osteoclasts, the bone-resorbing cells, in harboring C. burnetii during the infection. The histological analysis of bones from a murine model of Q fever revealed the presence of C. burnetii inside osteoclasts. In vitro infection assays confirmed that osteoclasts can be infected with C. burnetii and supported bacterial replication in a type IVB secretion system (T4BSS)-dependent manner. Wild-type C. burnetii infection inhibited osteoclast differentiation and bone-resorbing activity, while the T4BSS mutant enhanced the differentiation and bone-degrading function of osteoclasts. Taken together, our findings identify osteoclasts as a potential host cell for C. burnetii, opening new perspectives on mechanisms that may underlie chronic Q fever. Additionally, infection-induced alterations in osteoclast function raise the possibility of alterations of the bone structure in affected patients.

immunology↗

bioRxiv2025

Genomic insights into adaptation strategies and microevolutionary forces of novel non-AOA Nitrososphaeria in acid mine drainage ecosystems

The class Nitrososphaeria is best known for ammonia-oxidizing archaea (AOA), yet deeply branching non-AOA lineages remain poorly characterized, leaving a critical gap in our understanding of the groups early evolution and ecological diversification. Herein, we recovered 44 non-AOA Nitrososphaeria metagenome-assembled genomes (MAGs) from acid mine drainage (AMD) sediments in diverse metal mines, representing two novel genera within the family UBA164, Acidarchaeum and Thermosulfuris. A meta-analysis of 251 AMD-associated metagenomes showed that these potentially thermophilic lineages are globally distributed but typically rare, with local peaks ([~]6.6%) at sites such as Fankou. Metabolic reconstruction suggested a facultatively anaerobic, mixotrophic lifestyle capable of CO oxidation and sulfur reduction, and extensive acid- and heavy-metal resistance mediated primarily by ether-linked archaeal lipids, ion efflux systems, and enzymatic reduction. Genus-specific traits include dissimilatory sulfate reduction in Thermosulfuris and urea utilization in Acidarchaeum, illuminating distinct ecological niches for them. Population-genomic analyses reveal low homologous recombination and pervasive purifying selection in these non-AOA populations, together with local relaxation of selection and elevated diversity, the former being correlated with geochemical stressors (notably copper), pointing to long-term, geochemically driven adaptation. Overall, these findings provide insights into the biodiversity, ecophysiology, and evolutionary dynamics of non-AOA Nitrososphaeria. IMPORTANCEMembers of the class Nitrososphaeria that oxidize ammonia are central to the global nitrogen cycle, yet deep-branching lineages that lack this metabolism remain poorly explored, obscuring their early evolutionary trajectory. Here, we identify two new genera of non-ammonia-oxidizing Nitrososphaeria from acid mine drainage ecosystems and show that they recur globally in these acidic, metal-rich, oligotrophic habitats. Genomic analyses reveal adaptations for survival in harsh environments and genus-specific metabolic traits, suggesting distinct ecological strategies. Evolutionary analyses further indicate that these lineages are highly specialized, with population-genomic patterns consistent with long-term adaptation to geochemical conditions. This work sheds light on the biodiversity and evolutionary constraints of early-diverging lineages of Nitrososphaeria.

microbiology↗

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

scSTAR2: a multiomics integration algorithm to reveal disease specific cellular signatures by bridging single-cell resolution features and clinical metadata

Single-cell techniques, pivotal in characterizing intricate cell and spatial structures within tissues, face challenges in contextualizing clinical phenotypes. Currently, most investigations of the clinical phenotype related cell/spatial heterogeneities relied on the phenotype information from single-cell data. However, a wealth of underutilized clinical metadata exists within conventional bulk sequencing data. Current methods for correlating clinical information with individual cells or spatial regions remain limited and lack robustness. Here we present scSTAR2, a novel algorithm that transcends existing limitations by reconstructively integrating multiomics data to identify cells associated with clinical phenotypes. Unlike existing methods, scSTAR2 reconstructs single-cell data guided by specific phenotypes, significantly reducing interference from irrelevant noise. By employing scSTAR2 to integrate scRNA-seq, scATAC-seq, and spatial transcriptomics and bulk RNA-seq, we not only confirmed a new heat-shock Treg subtype in tumors but also more sensitively identified TLS (tertiary lymphoid structure) areas than traditional methods. In conclusion, scSTAR2 has proven to significantly enhance single-cell data interpretation across diverse clinical scenarios.

bioinformatics↗