Reverse-QTY code design of active human serum albumin self-assembled amphiphilic nanoparticles for effective anti-tumor drug doxorubicin release in mice.

Human serum albumin (HSA) is a highly water-soluble protein with 67% alpha-helix content and three distinct domains (I, II, and III). HSA offers a great promise in drug delivery with enhanced permeability and retention effect. But it is hindered by protein denaturation during drug entrapment or conjugation that result in distinct cellular transport pathways and reduction of biological activities. Here we report using a protein design approach named reverse-QTY (rQTY) code to convert specific hydrophilic alpha-helices to hydrophobic to alpha-helices. The designed HSA undergo self-assembly of well-ordered nanoparticles with highly biological actives. The hydrophilic amino acids, asparagine (N), glutamine (Q), threonine (T), and tyrosine (Y) in the helical B-subdomains of HSA were systematically replaced by hydrophobic leucine (L), valine (V), and phenylalanine (F). HSArQTY nanoparticles exhibited efficient cellular internalization through the cell membrane albumin binding protein GP60, or SPARC (secreted protein, acidic and rich in cysteine)-mediated pathways. The designed HSArQTY variants displayed superior biological activities including: i) encapsulation of drug doxorubicin, ii) receptor-mediated cellular transport, iii) tumor cell targeting, and iv) antitumor efficiency compare to denatured HSA nanoparticles. HSArQTY nanoparticles provided superior tumor targeting and antitumor therapeutic effects compared to the albumin nanoparticles fabricated by antisolvent precipitation method. We believe that the rQTY code is a robust platform for specific hydrophobic modification of functional hydrophilic proteins with clear-defined binding interfaces.

Assortative mating on blood type: Evidence from one million Chinese pregnancies.

Blood type is one of the most fundamental phenotypes in biological, medical, and psychological studies. Using a unique dataset of one million Chinese pregnancies, we find strong evidence from a group of statistical tests for assortative mating on blood type. After controlling for anthropometric and socioeconomic confounders, assortative mating remains robust.

Polystyrene nanoplastics enhance poxvirus preference for migrasome-mediated transmission.

Since the emergence of a global outbreak of mpox in 2022, understanding the transmission pathways and mechanisms of Orthopoxviruses, including vaccinia virus (VACV), has become paramount. Nanoplastic pollution has become a significant global issue due to its widespread presence in the environment and potential adverse effects on human health. These emerging pollutants pose substantial risks to both living organisms and the environment, raising serious health concerns related to their proliferation. Despite this, the effects of nanoparticles on viral transmission dynamics remain unclear. This study explores how polystyrene nanoparticles (PS-NPs) influence the transmission of VACV through migrasomes. We demonstrate that PS-NPs accelerate the formation of migrasomes early in the infection process, facilitating VACV entry as soon as 15 h post-infection (hpi), compared to the usual onset at 36 hpi. Immunofluorescence and transmission electron microscopy (TEM) reveal significant co-localization of VACV with migrasomes induced by PS-NPs by 15 hpi. This interaction coincides with an increase in lipid droplet size, attributed to higher cholesterol levels influenced by PS-NPs. By 36 hpi, migrasomes exposed to both PS-NPs and VACV exhibit distinct features, such as retraction fibers and larger lipid droplets, emphasizing their critical role in cargo transport during viral infections. These results suggest that PS-NPs may act as modulators of viral transmission dynamics through migrasomes, with potential implications for antiviral strategies and environmental health.

Smart Physical-Based Transdermal Drug Delivery System:Towards Intelligence and Controlled Release.

Transdermal drug delivery systems based on physical principles have provided a stable, efficient, and safe strategy for disease therapy. However, the intelligent device with real-time control and precise drug release is required to enhance treatment efficacy and improve patient compliance. This review summarizes the recent developments, application scenarios, and drug release characteristics of smart transdermal drug delivery systems fabricated with physical principle. Special attention is paid to the progress of intelligent design and concepts in of physical-based transdermal drug delivery technologies for real-time monitoring and precise drug release. In addition, facing with the needs of clinical treatment and personalized medicine, the recent progress and trend of physical enhancement are further highlighted for transdermal drug delivery systems in combination with pharmaceutical dosage forms to achieve better transdermal effects and facilitate the development of smart medical devices. Finally, the next generation and future application scenarios of smart physical-based transdermal drug delivery systems are discussed, a particular focus in vaccine delivery and tumor treatment.

Spatial-Temporal Transformer Networks for Traffic Flow Forecasting Using a Pre-Trained Language Model.

Most current methods use spatial-temporal graph neural networks (STGNNs) to analyze complex spatial-temporal information from traffic data collected from hundreds of sensors. STGNNs combine graph neural networks (GNNs) and sequence models to create hybrid structures that allow for the two networks to collaborate. However, this collaboration has made the model increasingly complex. This study proposes a framework that relies solely on original Transformer architecture and carefully designs embeddings to efficiently extract spatial-temporal dependencies in traffic flow. Additionally, we used pre-trained language models to enhance forecasting performance. We compared our new framework with current state-of-the-art STGNNs and Transformer-based models using four real-world traffic datasets: PEMS04, PEMS08, METR-LA, and PEMS-BAY. The experimental results demonstrate that our framework outperforms the other models in most metrics.

TGF-ß1 Triggers Salivary Hypofunction via Attenuating Protein Secretion and AQP5 Expression in Human Submandibular Gland Cells.

Aging-related salivary gland degeneration usually causes poor oral health. Periductal fibrosis frequently occurs in the submandibular gland of the elderly. Transforming growth factor ß1 (TGF-ß1) is the primary driving factor for fibrosis, which exhibits an increase in the fibrotic submandibular gland tissue. This study aimed to investigate the effects of TGF-ß1 on the human submandibular gland (HSG) cell secretory function and its influences on aquaporin 5 (AQP5) expressions and distribution. We found that TGF-ß1 reduces the protein secretion amount of HSG and leads to the abundance alteration of 151 secretory proteins. Data are available via ProteomeXchange with the identifier PXD043185. The majority of HSG secretory proteins (84.11%) could be matched to the human saliva proteome. Meanwhile, TGF-ß1 enhances the expression of COL4A2, COL5A1, COL7A1, COL1A1, COL2A1, and α-SMA, hinting that TGF-ß1 possesses the potential to drive HSG fibrosis-related events. Besides, TGF-ß1 also attenuates the AQP5 expression and its membrane distribution in HSGs. The percentage for TGF-ß1-induced AQP5 reduction (52.28%) is much greater than that of the TGF-ß1-induced secretory protein concentration reduction (16.53%). Taken together, we concluded that TGF-ß1 triggers salivary hypofunction via attenuating protein secretion and AQP5 expression in HSGs, which may be associated with TGF-ß1-driven fibrosis events in HSGs.

Bioinspired Robust Keratin Hydrogels for Biomedical Applications.

Although keratins are robust in nature, hydrogels producing their extracts exhibit poor mechanical properties due to the complicated composition and ineffective self-assembly. Here we report a bioinspired strategy to fabricate robust keratin hydrogels based on mechanism study through recombinant proteins. Homotypic and heterotypic self-assembly of selected type I and type II keratins in different combinations was conducted to identify crucial domain structures for the process, their kinetics, and relationship with the mechanical strength of hydrogels. Segments with best performance were isolated and used to construct novel assembling units. The new design outperformed combinations of native proteins in mechanical properties and in biomedical applications such as controlled drug release and skin regeneration. Our approach not only elucidated the critical structural domains and underlying mechanisms for keratin self-assembly but also opens an avenue toward the rational design of robust keratin hydrogels for biomedical applications.

QTL Mapping of Agronomic and Physiological Traits at the Seedling and Maturity Stages under Different Nitrogen Treatments in Barley.

Nitrogen (N) stress seriously constrains barley (Hordeum vulgare L.) production globally by influencing its growth and development. In this study, we used a recombinant inbred line (RIL) population of 121 crosses between the variety Baudin and the wild barley accession CN4027 to detect QTL for 27 traits at the seedling stage in hydroponic culture trials and 12 traits at the maturity stage in field trials both under two N treatments, aiming to uncover favorable alleles for N tolerance in wild barley. In total, eight stable QTL and seven QTL clusters were detected. Among them, the stable QTL Qtgw.sau-2H located in a 0.46 cM interval on the chromosome arm 2HL was a novel QTL specific for low N. Notably, Clusters C4 and C7 contained QTL for traits at both the seedling and maturity stages. In addition, four stable QTLs in Cluster C4 were identified. Furthermore, a gene (HORVU2Hr1G080990.1) related to grain protein in the interval of Qtgw.sau-2H was predicted. Correlation analysis and QTL mapping showed that different N treatments significantly affected agronomic and physiological traits at the seedling and maturity stages. These results provide valuable information for understanding N tolerance as well as breeding and utilizing the loci of interest in barley.

Revisiting financial development and renewable energy electricity role in attaining China's carbon neutrality target.

During the last few decades, China's transformation from a low-income country to an emerging economy causes carbon emission to rise extensively. Being the largest carbon emitter, China's continuous economic growth may inevitably cause more carbon emissions in the future. To achieve carbon neutrality targets, the country is striving to promote cleaner technologies. However, to finance these environmentally friendly projects, a well-developed financial system is a pre-requisite. This study examines the role of financial development along with output, financial risk index, renewable energy electricity and human capital on carbon emissions. This study uses updated time series data from 1988 to 2018 for China employing novel econometric approaches, i.e., Narayan and Pop unit root test with structural breaks, Maki cointegration and frequency domain causality test for long, short and medium run causality. The empirical outcome shows that improvement in financial development, renewable energy electricity, and human capital index cause to limit carbon emissions. In contrast, gross domestic product, financial risk index and structural break of 2001 increase carbon emissions. Moreover, structural break year of 2008 and financial development index reduces carbon emissions. The negative association between financial development and carbon emissions supports the positive school of thoughts of financial development that promotes a sustainable environment. This study recommends the promotion of quality human capital and green financial development along with increasing the shares of renewable energy in electricity for achieving China 2030 climate targets of reducing pollution.

Carbon neutrality target for G7 economies: Examining the role of environmental policy, green innovation and composite risk index.

To achieve zero carbon or achieving carbon neutrality target is of great importance to many countries around the globe especially post Paris climate agreement. This study, unlike previous studies, evaluates the role of environmental policy, green innovation, composite risk index, and renewable energy R&D in achieving carbon neutrality targets for G7 economies from 1990 to 2019. The results confirmed the validity of the EKC hypothesis for G7 economies. Further, the result shows that environmental policy, green innovation, composite risk index, and renewable energy R&D help control carbon emissions. In contrast, income reveals a positive influence on environmental degradation. Furthermore, bidirectional causality has been reported in environmental policy, composite risk index, green innovation, and the CO2 emissions, while unidirectional causality running from GDP and renewable energy R&D to CO2 emissions. Based on the empirical findings, it is suggested that environmental policies should be strengthened, promote green innovation and renewable energy research and development expenditures, and political stability and institutional quality must be stabilized to lowers sectoral risks that would help a sustainable environment.

Abnormal Galactosylated-Glycans recognized by Bandeiraea Simplicifolia Lectin I in saliva of patients with breast Cancer.

Currently, the definitive diagnosis in breast cancer requires biopsy and histopathology, such the most effective markers are tissue-based. However, the advantages of saliva in collection and storage make it possible for assessing human pathology and contributing to the development of cancer-related biomarkers for clinical application. The present study validated alteration of salivary protein glycopatterns recognized by Bandeiraea simplicifolia lectin I (BS-I) in the saliva of patients with breast diseases using saliva microarrays, and the N/O-glycan profiles of their salivary glycoproteins isolated by the BS-I-magnetic particle conjugates from 259 female subjects (66 healthy volunteers (HV), 65 benign breast cyst or tumor patients (BB), 66 patients with breast cancer in stage I (BC-I) and 62 patients with breast cancer in stage II (BC-II)) were analyzed by MALDI-TOF/TOF-MS. The results showed that the expression level of galactosylated glycans recognized by BS-I was significantly increased in patients with breast cancer compared with HV (p < 0.05). Totally, there were 11/10, 10/19, 7/24 and 7/9 galactosylated N-/O-linked glycans were identified and annotated from the pooled salivary samples of HV, BB, BC-I and BC-II, respectively. One galactosylated N-glycan peak (m/z 2773.977), and 4 galactosylated O-glycan peaks (m/z 868.295, 882.243, 884.270 and 1030.348) were found only in BC-I. These findings could provide pivotal information on galactosylated N/O-linked glycans related to breast cancer, and promote the study of biomarkers for early-stage breast cancer based on precise alterations of galactosylated N/O-glycans in saliva.

Effects of Alismatis rhizome on rat cytochrome P450 enzymes.

CONTEXT: Alismatis rhizome (RA) (Water Plantain Family, also called "Zexie" in Chinese), one of the commonly used components of traditional Chinese medicines, is derived from the dried rhizomes of Alisma orientalis (Sam.) Juzep. (Alismataceae). OBJECTIVE: This study explores the RA influences on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9, CYP2E1 and CYP3A4) by using cocktail probe drugs in vivo. MATERIALS AND METHODS: A cocktail solution at a dose of 5 mL/kg, which contained phenacetin (20 mg/kg), tolbutamide (5 mg/kg), chlorzoxazone (20 mg/kg) and midazolam (10 mg/kg), was orally administration to rats treated twice daily with RA (10, 20 and 40 g/kg) for consecutive 14 days. Blood samples (0.2 mL) were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0 (Wenzhou Medical College, Zhejiang, China). RESULTS: In the experiment, there was a statistically significant difference in the t1/2, Cmax, AUC(0-∞) and CL for phenacetin and midazolam, while there was no statistical pharmacokinetics difference for tolbutamide and chlorzoxazone. Our study showed that treatment with multiple doses of RA had an inductive effect on rat CYP1A2 and an inhibitory effect on rat CYP3A4 enzyme activity. However, RA has no inductive or inhibitory effect on the activities of CYP2C9 and CYP2E1. CONCLUSIONS: Caution is needed when RA is co-administration with some CYP1A2 or CYP3A4 substrates in clinic, because it may result in treatment failure and herb-drug interactions.

Facilitated transport of toluene and naphthalene with humic acid in high- and low-permeability systems: Role of ionic strength and cationic type.

The occurrence of colloids on pollutants transport in groundwater has attracted more attention. However, the research on the regulation mechanism of colloids on combined pollutants transport in heterogeneous aquifers is limited. In this study, a series of tank experiments were conducted to systematically investigate the effects of ionic strength, and cation type on humic acid (HA) facilitated transport of toluene (TOL), and naphthalene (NAP) in high- and low-permeability systems. The results showed that HA facilitated pollutants transport in low Na+ solution. In Ca2+ solution, the presence of HA hindered pollutants transport, and the inhibition increased with the increase of ionic strength. Both in Na+ solution and low Ca2+ solution, the influence of heterogeneous structure on pollutant transport played a dominant role, and TOL and NAP had a greater transport potential in the high permeability zone (HPZ) due to the preferential flow. Whereas, deposition of HA aggregates, and electrostatic attractive interaction had negative effects on transport than groundwater flow in high Ca2+ solution. Pollutants were prone to accumulate at the bottom of the HPZ, and the top of the low permeability zone (LPZ). These new findings provide insights into the mechanism of colloids influence on the pollutants transport in heterogenous aquifer.

Robotic-assisted anatomic anterior cruciate ligament reconstruction: a comparative analysis of modified transtibial and anteromedial portal techniques in cadaveric knees.

Introduction: This study employed surgical robot to perform anatomic single-bundle reconstruction using the modified transtibial (TT) technique and anteromedial (AM) portal technique. The purpose was to directly compare tunnel and graft characteristics of the two techniques. Methods: Eight cadaveric knees without ligament injury were used in the study. The modified TT and AM portal technique were both conducted under surgical robotic system. Postoperative data acquisition of the tunnel and graft characteristics included tibial tunnel position, tunnel angle, tunnel length and femoral tunnel-graft angle. Results: The mean tibial tunnel length of the modified TT technique was significantly shorter than in the AM portal technique (p < 0.001). The mean length of the femoral tunnel was significantly longer for the modified TT technique than for the AM portal technique (p < 0.001). The mean coronal angle of the tibial tunnel was significantly lower for the modified TT technique than for the AM portal technique (p < 0.001). The mean coronal angle of the femoral tunnel was significantly lower for the AM portal technique than for the modified TT technique (p < 0.001). The AM portal technique resulted in a graft bending angle that was significantly more angulated in the coronal (p < 0.001) and the sagittal planes (p < 0.001) compared with the modified TT technique. Discussion: Comparison of the preoperative planning and postoperative femoral tunnel positions showed that the mean difference of the tunnel position was 1.8 ± 0.4 mm. It suggested that the surgical navigation robot could make predictable tunnel position with high accuracy. The findings may support that the modified TT technique has benefits on femoral tunnel length and obliquity compared with AM portal technique. The modified TT technique showed a larger femoral tunnel angle in the coronal plane than the AM portal technique. Compared with the modified TT technique, the more horizontal trajectory of the femoral tunnel in the AM portal technique creates a shorter femoral tunnel length and a more acute graft bending angle.

miR-26a exerts broad-spectrum antiviral effects via the enhancement of RIG-I-mediated type I interferon response by targeting USP15.

IMPORTANCE: miR-26a serves as a potent positive regulator of type I interferon (IFN) responses. By inhibiting USP15 expression, miR-26a promotes RIG-I K63-ubiquitination to enhance type I IFN responses, resulting in an active antiviral state against viruses. Being an intricate regulatory network, the activation of type I IFN responses could in turn suppress miR-26a expression to avoid the disordered activation that might result in the so-called "type I interferonopathy." The knowledge gained would be essential for the development of novel antiviral strategies against viral infection.

Abnormalities in copper status associated with diminished ovarian reserve: A case-control and cross-sectional study.

OBJECTIVE: This study aimed to illustrate the copper status of diminished ovarian reserve in Chinese women, especially the effects of copper, ceruloplasmin, non-ceruloplasmin-bound copper (NCC) and CuZn superoxide dismutase (SOD1). METHODS: This case-control, cross-sectional investigation included women with diminished ovarian reserve (DOR group, n = 35) and matched normal ovarian reserve (NOR group, n = 35). The serum levels of copper, ceruloplasmin, NCC, SOD1, follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone, and anti-Müllerian hormone were tested and analyzed. RESULTS: The serum copper concentrations (60.88%), NCC (54.75%) and SOD1 (54.75%) in the DOR group were significantly higher than those in the NOR group (all P < 0.001), and the concentrations of the three markers were higher in most subgroups (P < 0.001). The correlation analysis verified the correlation between copper status and impaired ovarian function. Additionally, linear regression analysis showed that NCC and SOD1 levels were negatively correlated with anti-Müllerian hormone (P < 0.05 or 0.001). CONCLUSION: Our exploration found significant increases in copper, NCC and SOD1 levels in DOR and suggests a possible link. Copper status is expected to serve as the predictive marker for DOR.

Lung decellularized matrix-derived 3D spheroids: Exploring silicosis through the impact of the Nrf2/Bax pathway on myofibroblast dynamics.

Silicosis is an occupational respiratory disease caused by long-term inhalation of high concentrations of free silica particles. Studies suggest that oxidative stress is a crucial initiator of silicosis fibrosis, and previous studies have linked the antioxidative stress transcription factor known as Nrf2 to fibrosis antagonism. Myofibroblasts play a pivotal role in tissue damage repair due to oxidative stress. Unlike physiological repair, myofibroblasts in fibrosis exhibit an apoptosis-resistant phenotype, continuously synthesising and secreting significant amounts of collagen and other extracellular matrices, which could be a direct cause of silicosis fibrosis. However, the relationship and mechanism of action between oxidative stress and myofibroblast apoptosis resistance remain unclear. In this study, a new 3D cell culture model using mice lung decellularised matrix particles and fibroblasts was developed, simulating the changes in myofibroblasts during the development of silicotic nodules. Western Blot results indicate that silica stimulation leads to increased collagen deposition and decreased apoptosis-related protein Bax and oxidative stress-related protein Nrf2 in the 3D spheroid model. Immunofluorescence experiments reveal co-localisation in their expression. In Nrf2 overexpressing spheroids, Bax exhibits significant upregulation. In the Nrf2 knockout spheroids, Bax is also significantly downregulated; after intervention with Bax inhibitors, a significant downregulation of Bax-induced apoptosis was also detected in the Nrf2-overexpressed spheroids. In contrast, Bax-induced apoptosis showed a significant upregulation trend in Nrf2-overexpressed spheroids after intervention with Bax agonists. The results demonstrate that the spheroid model can mimic the development process of silicotic nodules, and silica stimulation leads to an apoptosis-resistant phenotype in myofibroblasts in the model, acting through the Nrf2/Bax pathway. This research establishes a new methodology for silicosis study, identifies therapeutic targets for silicosis, and opens new avenues for studying the mechanisms of silicosis fibrosis.

QTL Mapping of Yield, Agronomic, and Nitrogen-Related Traits in Barley (Hordeum vulgare L.) under Low Nitrogen and Normal Nitrogen Treatments.

Improving low nitrogen (LN) tolerance in barley (Hordeum vulgare L.) increases global barley yield and quality. In this study, a recombinant inbred line (RIL) population crossed between "Baudin × CN4079" was used to conduct field experiments on twenty traits of barley yield, agronomy, and nitrogen(N)-related traits under LN and normal nitrogen (NN) treatments for two years. This study identified seventeen QTL, comprising eight QTL expressed under both LN and NN treatments, eight LN-specific QTL, and one NN-specific QTL. The localized C2 cluster contained QTL controlling yield, agronomic, and N-related traits. Of the four novel QTL, the expression of the N-related QTL Qstna.sau-5H and Qnhi.sau-5H was unaffected by N treatment. Qtgw.sau-2H for thousand-grain weight, Qph.sau-3H for plant height, Qsl.sau-7H for spike length, and Qal.sau-7H for awn length were identified to be the four stable expression QTL. Correlation studies revealed a significant negative correlation between grain N content and harvest index (p < 0.01). These results are essential for barley marker-assisted selection (MAS) breeding.

Molecular determinants within the C-termini of L-HDAg that regulate hepatitis D virus replication and assembly.

Background & Aims: Hepatitis D virus (HDV) is the causative agent of chronic hepatitis delta, the most severe form of viral hepatitis. HDV encodes one protein, hepatitis delta antigen (HDAg), in two isoforms: S- and L-HDAg. They are identical in sequence except that L-HDAg contains an additional 19-20 amino acids at its C-terminus, which confer regulatory roles that are distinct from those of S-HDAg. Notably, these residues are divergent between different genotypes. We aimed to elucidate the molecular determinants within the C-termini that are essential for the regulatory role of L-HDAg in HDV replication and assembly. Methods: Northern blot, reverse-transcription quantitative PCR, and a newly established HDV trans-complementary system were used in this study. Results: C-termini of L-HDAg, albeit with high sequence variation among different genotypes, are interchangeable with respect to the trans-inhibitory function of L-HDAg and HDV assembly. The C-terminus of L-HDAg features a conserved prenylation CXXQ motif and is enriched with proline and hydrophobic residues. Abolishment of the CXXQ motif attenuated the inhibitory effect of L-HDAg on HDV replication. In contrast, the enrichment of proline and hydrophobic residues per se does not modify the trans-inhibitory function of L-HDAg. Nevertheless, these residues are essential for HDV assembly. Mechanistically, prolines and hydrophobic residues contribute to HDV assembly via a mode of action independent of the prenylated CXXQ motif. Conclusions: Within the C-terminus of L-HDAg, the CXXQ motif and the enrichment of proline and hydrophobic residues are all essential determinants of L-HDAg's regulatory roles in HDV replication and assembly. This intrinsic viral regulatory mechanism we elucidated deepens our understanding of the unique life cycle of HDV. Impact and implications: Hepatitis D virus (HDV) encodes one protein, hepatitis delta antigen (HDAg), in two isoforms: S- and L-HDAg. They are identical in sequence except that L-HDAg contains an additional 19-20 amino acids at its C-terminus. This C-terminal extension in L-HDAg confers regulatory roles in the HDV life cycle that are distinct from those of S-HDAg. Herein, we found that C-termini of L-HDAg, although with high sequence variation, are interchangeable among different HDV genotypes. Within the C-terminus of L-HDAg, the prenylation motif, and the enrichment of proline and hydrophobic residues are all essential determinants of L-HDAg's regulatory roles in HDV replication and assembly.

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions.

Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC50 value of vidofludimus calcium is 4.6-7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-α resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.