Biology subjects

Zuo, R.

Publications and source records attributed to Zuo, R..

4 recordsLinked to original sources

bioRxiv2026

An LSEC-focused computational drug repurposing platform for liver fibrosis: Identification of vorinostat and other LSEC-protective candidates

Liver sinusoidal endothelial cells (LSECs) are increasingly recognized as a critical yet underexplored cell type in anti-fibrotic drug development. This study presents a computational drug screening platform integrating LSEC-specific transcriptomic analysis across simple steatosis, fibrotic nonalcoholic steatohepatitis (NASH), and cirrhosis, with tiered gene signature selection combining machine learning, large language model-assisted curation, gene safety assessment, and Connectivity Map-based screening using human endothelial perturbational profiles. The platform identifies 6 clinical-stage and 8 preclinical candidates with LSEC-protective potential. Among these, vorinostat (SAHA), a clinically approved histone deacetylase (HDAC) inhibitor, is selected for experimental validation. In hepatocyte-specific Asah1-deficient mice fed a Paigen diet, SAHA attenuates hepatic inflammation, fibrosis, LSEC dysfunction, and portal hemodynamic abnormalities, with effects confirmed in a hepatotoxin (CCl4)-induced fibrosis model. High mobility group box 1 (HMGB1) is identified as a key hepatocyte-derived paracrine mediator of LSEC injury through Transwell co-culture and glycyrrhizin rescue. Vorinostat dose-dependently reverses HMGB1-induced LSEC dysfunction across inflammation, capillarization, fibrogenesis, and vasoconstriction, associated with endothelial transcription factor reprogramming including KLF2 upregulation, validated in primary LSECs and in vivo. SAHA also protected LSECs from TNF--induced inflammation and reduced monocyte adhesion. These findings establish an LSEC-focused drug repurposing framework and identify candidates for LSEC-protective anti-fibrotic therapy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/727430v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@41e95dorg.highwire.dtl.DTLVardef@1401031org.highwire.dtl.DTLVardef@e72fc4org.highwire.dtl.DTLVardef@1f11347_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

N6-Methyladenosine Safeguards Mouse and Human Germline Competence

N6-Methyladenosine (m6A) regulation of germline entry in post-implantation-like-pluripotent states remains poorly defined. We characterized m6A depletion by Mettl3 or Mettl14 knock-down or METTL3 inhibition in in vitro models enabling primordial germ-cell-like-cell and somatic differentiation. Upon m6A depletion, mouse epiblast-like cells upregulated embryonic Ras (Eras) and PI3K-pAKT, facilitating EZH2 repression and depletion of H3K27me3. Consequently, enhancer activation promoted global gene deregulation and impaired germline entry. In mouse formative stem cells, ERAS-PI3K-pAKT upregulation resulted in unscheduled Blimp1 and Otx2 co-expression, germline entry deficiency and enhanced mesodermal differentiation. Conversely, upon m6A depletion, germline competent human pluripotent stem cells upregulated OTX2 through FGF-pERK activation, resulting in germline entry deficiency and enhanced neuroectodermal differentiation. meRIP-seq revealed preferential m6A deposition on mouse mesodermal and human neuroectodermal transcripts, suggesting a basis for differentiation bias following m6A depletion. We illustrate how decreasing m6A abundances impact signaling, chromatin epigenetics and transcript stabilities, constituting a powerful cell intrinsic barrier for germline entry.

developmental biology↗

bioRxiv2024

Coronary Microvascular Dysfunction is Associated with Augmented Lysosomal Signaling in Hypercholesterolemic Mice

Accumulating evidence indicates that coronary microvascular dysfunction (CMD) caused by hypercholesterolemia can lead to myocardial ischemia, with or without obstructive atherosclerotic coronary artery disease (CAD). However, the molecular pathways associated with compromised coronary microvascular function prior to the development of myocardial ischemic injury remain poorly defined. In this study, we investigated the effects of hypercholesterolemia on the function and integrity of the coronary microcirculation in mice and the underlying mechanisms. Mice were fed with a hypercholesterolemic Paigens diet (PD) for 8 weeks. Echocardiography data showed that PD caused CMD, characterized by significant reductions in coronary blood flow and coronary flow reserve (CFR), but did not affect cardiac remodeling or dysfunction. Immunofluorescence studies revealed that PD-induced CMD was associated with activation of coronary arterioles inflammation and increased myocardial inflammatory cell infiltration. These pathological changes occurred in parallel with the upregulation of lysosomal signaling pathways in endothelial cells (ECs). Treating hypercholesterolemic mice with the cholesterol-lowering drug ezetimibe significantly ameliorated PD-induced adverse effects, including hypercholesterolemia, steatohepatitis, reduced CFR, coronary EC inflammation, and myocardial inflammatory cell infiltration. In cultured mouse cardiac endothelial cells (MCECs), 7-ketocholesterol (7K) increased mitochondrial reactive oxygen species (ROS) and inflammatory responses. Meanwhile, 7K induced the activation of TFEB and lysosomal signaling in MCECs, whereas the lysosome inhibitor bafilomycin A1 blocked 7K-induced TFEB activation and exacerbated 7K-induced inflammation and cell death. Interestingly, ezetimibe synergistically enhanced 7K-induced TFEB activation and attenuated 7K-induced mitochondrial ROS and inflammatory responses in MCECs. These results suggest that CMD can develop and precede detectable cardiac functional or structural changes in the setting of hypercholesterolemia, and that upregulation of TFEB-mediated lysosomal signaling in ECs plays a protective role against CMD.

pharmacology and toxicology↗

bioRxiv2023

Angiopoietin-like 4 promotes the proliferation and migration of epidermal stem cells and contributes to the re-epithelialization of cutaneous wounds

Proliferation and migration of epidermal stem cells (EpSCs) are essential for epithelialization during skin wound healing. Angiopoietin-like 4 (ANGPTL4) has been reported to play an important role in wound healing, but the mechanisms involved are not fully understood. Here we investigate the contribution of ANGPTL4 to full-thickness wound re-epithelialization and the underlying mechanisms using Angptl4 knockout mice. Immunohistochemical staining reveals that ANGPTL4 is significantly upregulated in the basal layer cells of the epidermis around the wound during cutaneous wound healing. ANGPTL4 deficiency impairs wound healing. H & E staining shows that ANGPTL4 deficiency significantly reduces the thickness, length and area of regenerated epidermis postwounding. Immunohistochemical staining for markers of EpSCs (6 integrin and {beta}1 integrin) and cell proliferation (PCNA) shows that the number and proliferation of EpSCs in the basal layer of the epidermis are reduced in ANGPTL4-deficient mice. In vitro studies show that ANGPTL4 deficiency impedes EpSC proliferation, causes cell cycle arrest at the G1 phase and reduced the expression of cyclins D1 and A2, which can be reversed by ANGPTL4 overexpression. ANGPTL4 deletion suppresses EpSC migration, which is also rescued by ANGPTL4 overexpression. Overexpression of ANGPTL4 in EpSCs accelerates cell proliferation and migration. Collectively, our results indicate that ANGPTL4 promotes EpSCs proliferation by upregulating cyclins D1 and A2 expression and accelerating cell cycle transition from G1 to S phase, and ANGPTL4 promotes skin wound re-epithelialization by stimulating EpSC proliferation and migration. Our study reveals a novel mechanism underlying EpSC activation and re-epithelialization during cutaneous wound healing.

cell biology↗