Structural and functional characterizations of infectivity and immune evasion of SARS-CoV-2 Omicron.

The SARS-CoV-2 Omicron variant with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the spike (S) from Omicron reveals amino acid substitutions forging interactions that stably maintain an active conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of the viral fusion step. Alterations in local conformation, charge, and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Structure of the Omicron S bound with human ACE2, together with the analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members, as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies, sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.

Close relatives of MERS-CoV in bats use ACE2 as their functional receptors.

Middle East respiratory syndrome coronavirus (MERS-CoV) and several bat coronaviruses use dipeptidyl peptidase-4 (DPP4) as an entry receptor1-4. However, the receptor for NeoCoV-the closest known MERS-CoV relative found in bats-remains unclear5. Here, using a pseudotype virus entry assay, we found that NeoCoV and its close relative, PDF-2180, can efficiently bind to and use specific bat angiotensin-converting enzyme 2 (ACE2) orthologues and, less favourably, human ACE2 as entry receptors through their receptor-binding domains (RBDs) on the spike (S) proteins. Cryo-electron microscopy analysis revealed an RBD-ACE2 binding interface involving protein-glycan interactions, distinct from those of other known ACE2-using coronaviruses. We identified residues 337-342 of human ACE2 as a molecular determinant restricting NeoCoV entry, whereas a NeoCoV S pseudotyped virus containing a T510F RBD mutation efficiently entered cells expressing human ACE2. Although polyclonal SARS-CoV-2 antibodies or MERS-CoV RBD-specific nanobodies did not cross-neutralize NeoCoV or PDF-2180, an ACE2-specific antibody and two broadly neutralizing betacoronavirus antibodies efficiently inhibited these two pseudotyped viruses. We describe MERS-CoV-related viruses that use ACE2 as an entry receptor, underscoring a promiscuity of receptor use and a potential zoonotic threat.

Memory B cell repertoire from triple vaccinees against diverse SARS-CoV-2 variants.

Omicron (B.1.1.529), the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising concerns about the effectiveness of antibody therapies and vaccines1,2. Here we examined whether sera from individuals who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2 out of 60) and 95% (57 out of 60) for individuals who had received 2 and 3 doses of vaccine, respectively. For recipients of three vaccine doses, the geometric mean neutralization antibody titre for Omicron was 16.5-fold lower than for the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in triple vaccinees, half of which recognized the receptor-binding domain, and showed that a subset (24 out of 163) potently neutralized all SARS-CoV-2 variants of concern, including Omicron. Therapeutic treatments with representative broadly neutralizing monoclonal antibodies were highly protective against infection of mice with SARS-CoV-2 Beta (B.1.351) and Omicron. Atomic structures of the Omicron spike protein in complex with three classes of antibodies that were active against all five variants of concern defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to a class of antibodies that bind on the right shoulder of the receptor-binding domain by altering local conformation at the binding interface. Our results rationalize the use of three-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are rational targets for a universal sarbecovirus vaccine.

mEnrich-seq: methylation-guided enrichment sequencing of bacterial taxa of interest from microbiome.

Metagenomics has enabled the comprehensive study of microbiomes. However, many applications would benefit from a method that sequences specific bacterial taxa of interest, but not most background taxa. We developed mEnrich-seq (in which 'm' stands for methylation and seq for sequencing) for enriching taxa of interest from metagenomic DNA before sequencing. The core idea is to exploit the self versus nonself differentiation by natural bacterial DNA methylation and rationally choose methylation-sensitive restriction enzymes, individually or in combination, to deplete host and background taxa while enriching targeted taxa. This idea is integrated with library preparation procedures and applied in several applications to enrich (up to 117-fold) pathogenic or beneficial bacteria from human urine and fecal samples, including species that are hard to culture or of low abundance. We assessed 4,601 bacterial strains with mapped methylomes so far and showed broad applicability of mEnrich-seq. mEnrich-seq provides microbiome researchers with a versatile and cost-effective approach for selective sequencing of diverse taxa of interest.

MkcDBGAS: a reference-free approach to identify comprehensive alternative splicing events in a transcriptome.

Alternative splicing (AS) is an essential post-transcriptional mechanism that regulates many biological processes. However, identifying comprehensive types of AS events without guidance from a reference genome is still a challenge. Here, we proposed a novel method, MkcDBGAS, to identify all seven types of AS events using transcriptome alone, without a reference genome. MkcDBGAS, modeled by full-length transcripts of human and Arabidopsis thaliana, consists of three modules. In the first module, MkcDBGAS, for the first time, uses a colored de Bruijn graph with dynamic- and mixed- kmers to identify bubbles generated by AS with precision higher than 98.17% and detect AS types overlooked by other tools. In the second module, to further classify types of AS, MkcDBGAS added the motifs of exons to construct the feature matrix followed by the XGBoost-based classifier with the accuracy of classification greater than 93.40%, which outperformed other widely used machine learning models and the state-of-the-art methods. Highly scalable, MkcDBGAS performed well when applied to Iso-Seq data of Amborella and transcriptome of mouse. In the third module, MkcDBGAS provides the analysis of differential splicing across multiple biological conditions when RNA-sequencing data is available. MkcDBGAS is the first accurate and scalable method for detecting all seven types of AS events using the transcriptome alone, which will greatly empower the studies of AS in a wider field.

The RNA-Splicing Ligase RTCB Promotes Influenza A Virus Replication by Suppressing Innate Immunity via Interaction with RNA Helicase DDX1.

The RNA-splicing ligase RNA 2',3'-cyclic phosphate and 5'-OH ligase (RTCB) is a catalytic subunit of the tRNA-splicing ligase complex, which plays an essential role in catalyzing tRNA splicing and modulating the unfolded protein response. However, the function of RTCB in influenza A virus (IAV) replication has not yet been described. In this study, RTCB was revealed to be an IAV-suppressed host factor that was significantly downregulated during influenza virus infection in several transformed cell lines, as well as in primary human type II alveolar epithelial cells, and its knockout impaired the propagation of the IAV. Mechanistically, RTCB depletion led to a robust elevation in the levels of type I and type III IFNs and proinflammatory cytokines in response to IAV infection, which was confirmed by RTCB overexpression studies. Lastly, RTCB was found to compete with DDX21 for RNA helicase DDX1 binding, attenuating the DDX21-DDX1 association and thus suppressing the expression of IFN and downstream IFN-stimulated genes. Our study indicates that RTCB plays a critical role in facilitating IAV replication and reveals that the RTCB-DDX1 binding interaction is an important innate immunomodulator for the host to counteract viral infection.

Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition.

Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural beta-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.

Role of gasotransmitters in necroptosis.

Gasotransmitters are endogenous gaseous signaling molecules that can freely pass through cell membranes and transmit signals between cells, playing multiple roles in cell signal transduction. Due to extensive and ongoing research in this field, we have successfully identified many gasotransmitters so far, among which nitric oxide, carbon monoxide, and hydrogen sulfide are best studied. Gasotransmitters are implicated in various diseases related to necroptosis, such as cardiovascular diseases, inflammation, ischemia-reperfusion, infectious diseases, and neurological diseases. However, the mechanisms of their effects on necroptosis are not fully understood. This review focuses on endogenous gasotransmitter synthesis and metabolism and discusses their roles in necroptosis, aiming to offer new insights for the therapeutic approaches to necroptosis-associated diseases.

Gene therapy approaches for obesity-induced adipose neuropathy: Device-targeted AAV-mediated neurotrophic factor delivery to adipocytes in subcutaneous adipose.

Maintaining functional adipose innervation is critical for metabolic health. We found that subcutaneous white adipose tissue (scWAT) undergoes peripheral neuropathy (PN) with obesity, diabetes, and aging (reduced small-fiber innervation and nerve/synaptic/growth-cone/vesicle markers, altered nerve activity). Unlike with nerve injuries, peripheral nerves do not regenerate with PN, and therefore new therapies are needed for treatment of this condition affecting 20-30 million Americans. Here, we validated a gene therapy approach using an adipocyte-tropic adeno-associated virus (AAV; serotype Rec2) to deliver neurotrophic factors (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) directly to scWAT to improve tissue-specific PN as a proof-of-concept approach. AAVRec2-BDNF intra-adipose delivery improved tissue innervation in obese/diabetic mice with PN, but after longer periods of dietary obesity there was reduced efficacy, revealing a key time window for therapies. AAVRec2-NGF also increased scWAT innervation in obese mice and was more effective than BDNF, likely because Rec2 targeted adipocytes, the tissue's endogenous NGF source. AAVRec2-NGF also worked well even after 25 weeks of dietary obesity, unlike BDNF, which likely needs a vector that targets its physiological cellular source (stromal vascular fraction cells). Given the differing effects of AAVs carrying NGF versus BDNF, a combined therapy may be ideal for PN.

Somatostatin signalling coordinates energy metabolism allocation to reproduction in zebrafish.

BACKGROUND: Energy allocation between growth and reproduction determines puberty onset and fertility. In mammals, peripheral hormones such as leptin, insulin and ghrelin signal metabolic information to the higher centres controlling gonadotrophin-releasing hormone neurone activity. However, these observations could not be confirmed in lower vertebrates, suggesting that other factors may mediate the energetic trade-off between growth and reproduction. A bioinformatic and experimental study suggested co-regulation of the circadian clock, reproductive axis and growth-regulating genes in zebrafish. While loss-of-function of most of the identified co-regulated genes had no effect or only had mild effects on reproduction, no such information existed about the co-regulated somatostatin, well-known for its actions on growth and metabolism. RESULTS: We show that somatostatin signalling is pivotal in regulating fecundity and metabolism. Knock-out of zebrafish somatostatin 1.1 (sst1.1) and somatostatin 1.2 (sst1.2) caused a 20-30% increase in embryonic primordial germ cells, and sst1.2-/- adults laid 40% more eggs than their wild-type siblings. The sst1.1-/- and sst1.2-/- mutants had divergent metabolic phenotypes: the former had 25% more pancreatic α-cells, were hyperglycaemic and glucose intolerant, and had increased adipocyte mass; the latter had 25% more pancreatic ß-cells, improved glucose clearance and reduced adipocyte mass. CONCLUSIONS: We conclude that somatostatin signalling regulates energy metabolism and fecundity through anti-proliferative and modulatory actions on primordial germ cells, pancreatic insulin and glucagon cells and the hypothalamus. The ancient origin of the somatostatin system suggests it could act as a switch linking metabolism and reproduction across vertebrates. The results raise the possibility of applications in human and animal fertility.

Enhancing head and neck tumor management with artificial intelligence: Integration and perspectives.

Head and neck tumors (HNTs) constitute a multifaceted ensemble of pathologies that primarily involve regions such as the oral cavity, pharynx, and nasal cavity. The intricate anatomical structure of these regions poses considerable challenges to efficacious treatment strategies. Despite the availability of myriad treatment modalities, the overall therapeutic efficacy for HNTs continues to remain subdued. In recent years, the deployment of artificial intelligence (AI) in healthcare practices has garnered noteworthy attention. AI modalities, inclusive of machine learning (ML), neural networks (NNs), and deep learning (DL), when amalgamated into the holistic management of HNTs, promise to augment the precision, safety, and efficacy of treatment regimens. The integration of AI within HNT management is intricately intertwined with domains such as medical imaging, bioinformatics, and medical robotics. This article intends to scrutinize the cutting-edge advancements and prospective applications of AI in the realm of HNTs, elucidating AI's indispensable role in prevention, diagnosis, treatment, prognostication, research, and inter-sectoral integration. The overarching objective is to stimulate scholarly discourse and invigorate insights among medical practitioners and researchers to propel further exploration, thereby facilitating superior therapeutic alternatives for patients.

MCM8 promotes lung cancer progression through upregulating DNAJC10.

MCM8 is a helicase, which participates in DNA replication and tumorigenesis and is upregulated in many human cancers, including lung cancer (LC); however, the function of MCM8 in LC tumour progression is unclear. In this study, we found that MCM8 was expressed at high levels in LC cells and tissues. Further, MCM8 upregulation was associated with advanced tumour grade and lymph node metastasis, and indicated poor prognosis. Silencing of MCM8 suppressed cell growth and migration in vitro and in vivo, while ectopic MCM8 expression promoted cell cycle progression, as well as cell migration, proliferation, and apoptosis. Mechanistically, DNAJC10 was identified as a downstream target of MCM8, using gene array and CO-IP assays. DNAJC10 overexpression combatted the inhibitory activity of MCM8 knockdown on LC progression, while silencing DNAJC10 alleviated the oncogenic function of MCM8 overexpression. MCM8 expression was positively correlated with that of DNAJC10 in LC samples from The Cancer Genome Atlas database, and DNAJC10 upregulation was also associated with poor overall survival of patients with LC. This study indicated that MCM8/DNAJC10 axis plays an important role in in LC development, and maybe as a new potential therapeutic target or a diagnostic biomarker for treating patients with LC.

The disordered C terminus of ALKBH5 promotes phase separation and paraspeckles assembly.

Paraspeckles (PS) are nuclear structures scaffolded by the long noncoding RNA NEAT1 and protein components such as NONO and SFPQ. We previously found that the upregulation of RNA N6-methyl-adenosine (m6A) demethylase ALKBH5 facilitates hypoxia-induced paraspeckle assembly through erasing m6A marks on NEAT1, thus stabilizing it. However, it remains unclear how these processes are spatiotemporally coordinated. Here we discover that ALKBH5 specifically binds to proteins in PS and forms phase-separated droplets that are incorporated into PS through its C-terminal intrinsically disordered region (cIDR). Upon exposure to hypoxia, rapid ALKBH5 condensation in PS induces m6A demethylation of NEAT1, which further facilitates PS formation before the upregulation of ALKBH5 expression. In cells expressing ALKBH5 lacking cIDR, PS fail to be formed in response to hypoxia, accompanied with insufficient m6A demethylation of NEAT1 and its destabilization. We also demonstrate that ALKBH5-cIDR is indispensable for hypoxia-induced effects such as cancer cell invasion. Therefore, our study has identified the role of ALKBH5 in phase separation as the molecular basis of the positive feedback loop for PS formation between ALKBH5 incorporation into PS and NEAT1 stabilization.

Long-term effects of a fat-directed FGF21 gene therapy in aged female mice.

Fibroblast growth factor 21 (FGF21) has been developed as a potential therapeutic agent for metabolic syndromes. Moreover, FGF21 is considered a pro-longevity hormone because transgenic mice overexpressing FGF21 display extended lifespan, raising the possibility of using FGF21 to promote healthy aging. We recently showed that visceral fat directed FGF21 gene therapy improves metabolic and immune health in insulin resistant BTBR mice. Here, we used a fat directed rAAV-FGF21 vector in 17-month-old female mice to investigate whether long-term FGF21 gene transfer could mitigate aging-related functional decline. Animals with FGF21 treatment displayed a steady, significant lower body weight over 7-month of the study compared to age-matched control mice. FGF21 treatment reduced adiposity and increased relative lean mass and energy expenditure associated with almost 100 folds higher serum level of FGF21. However, those changes were not translated into benefits on muscle function and did not affect metabolic function of liver. Overall, we have demonstrated that a single dose of fat-directed AAV-FGF21 treatment can provide a sustainable, high serum level of FGF21 over long period of time, and mostly influences adipose tissue homeostasis and energy expenditure. High levels of FGF21 alone in aged mice is not sufficient to improve liver or muscle functions.

Passivating Grain Boundaries via Graphene Additive for Efficient Kesterite Solar Cells.

Grain boundaries (GBs)-triggered severe non-radiative recombination is recently recognized as the main culprits for carrier loss in polycrystalline kesterite photovoltaic devices. Accordingly, further optimization of kesterite-based thin film solar cells critically depends on passivating the grain interfaces of polycrystalline Cu2 ZnSn(S,Se)4 (CZTSSe) thin films. Herein, 2D material of graphene is first chosen as a passivator to improve the detrimental GBs. By adding graphene dispersion to the CZTSSe precursor solution, single-layer graphene is successfully introduced into the GBs of CZTSSe absorber. Due to the high carrier mobility and electrical conductivity of graphene, GBs in the CZTSSe films are transforming into electrically benign and do not act as high recombination sites for carrier. Consequently, benefitting from the significant passivation effect of GBs, the use of 0.05 wt% graphene additives increases the efficiency of CZTSSe solar cells from 10.40% to 12.90%, one of the highest for this type of cells. These results demonstrate a new route to further increase kesterite-based solar cell efficiency by additive engineering.

Nanoparticles Targeting Lymph Nodes for Cancer Immunotherapy: Strategies and Influencing Factors.

Immunotherapy has emerged as a potent strategy in cancer treatment, with many approved drugs and modalities in the development stages. Despite its promise, immunotherapy is not without its limitations, including side effects and suboptimal efficacy. Using nanoparticles (NPs) as delivery vehicles to target immunotherapy to lymph nodes (LNs) can improve the efficacy of immunotherapy drugs and reduce side effects in patients. In this context, this paper reviews the development of LN-targeted immunotherapeutic NP strategies, the mechanisms of NP transport during LN targeting, and their related biosafety risks. NP targeting of LNs involves either passive targeting, influenced by NP physical properties, or active targeting, facilitated by affinity ligands on NP surfaces, while alternative methods, such as intranodal injection and high endothelial venule (HEV) targeting, have uncertain clinical applicability and require further research and validation. LN targeting of NPs for immunotherapy can reduce side effects and increase biocompatibility, but risks such as toxicity, organ accumulation, and oxidative stress remain, although strategies such as biodegradable biomacromolecules, polyethylene glycol (PEG) coating, and impurity addition can mitigate these risks. Additionally, this work concludes with a future-oriented discussion, offering critical insights into the field.

Energetic trade-offs in migration decision-making, reproductive effort and subsequent parental care in a long-distance migratory bird.

Migratory species trade-off long-distance movement with survival and reproduction, but the spatio-temporal scales at which these decisions occur are relatively unknown. Technological and statistical advances allow fine-scale study of animal decision-making, improving our understanding of possible causes and therefore conservation management. We quantified effects of reproductive preparation during spring migration on subsequent breeding outcomes, breeding outcomes on autumn migration characteristics and autumn migration characteristics on subsequent parental survival in Greenland white-fronted geese (Anser albifrons flavirostris). These are long-distance migratory birds with an approximately 50% population decline from 1999 to 2022. We deployed GPS-acceleration devices on adult females to quantify up to 5 years of individual decision-making throughout the annual cycle. Weather and habitat-use affected time spent feeding and overall dynamic body acceleration (i.e. energy expenditure) during spring and autumn. Geese that expended less energy and fed longer during spring were more likely to successfully reproduce. Geese with offspring expended more energy and fed for less time during autumn, potentially representing adverse fitness consequences of breeding. These behavioural comparisons among Greenland white-fronted geese improve our understanding of fitness trade-offs underlying abundance. We provide a reproducible framework for full annual cycle modelling using location and behaviour data, applicable to similarly studied migratory animals.

Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway.

AIMS: Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. METHODS AND RESULTS: We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. CONCLUSIONS: These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.

PM10 exposure induces bronchial hyperresponsiveness by upreguating acetylcholine muscarinic 3 receptor.

Exposure to particulate matter (PM10) can induce respiratory diseases that are closely related to bronchial hyperresponsiveness. However, the involved mechanism remains to be fully elucidated. This study aimed to demonstrate the effects of PM10 on the acetylcholine muscarinic 3 receptor (CHRM3) expression and the role of the ERK1/2 pathway in rat bronchial smooth muscle. A whole-body PM10 exposure system was used to stimulate bronchial hyperresponsiveness in rats for 2 and 4 months, accompanied by MEK1/2 inhibitor U0126 injection. The whole-body plethysmography system and myography were used to detect the pulmonary and bronchoconstrictor function, respectively. The mRNA and protein levels were determined by Western blotting, qPCR, and immunofluorescence. Enzyme-linked immunosorbent assay was used to detect the inflammatory cytokines. Compared with the filtered air group, 4 months of PM10 exposure significantly increased CHRM3-mediated pulmonary function and bronchial constriction, elevated CHRM3 mRNA and protein expression levels on bronchial smooth muscle, then induced bronchial hyperreactivity. Additionally, 4 months of PM10 exposure caused an increase in ERK1/2 phosphorylation and increased the secretion of inflammatory factors in bronchoalveolar lavage fluid. Treatment with the MEK1/2 inhibitor, U0126 inhibited the PM10 exposure-induced phosphorylation of the ERK1/2 pathway, thereby reducing the PM10 exposure-induced upregulation of CHRM3 in bronchial smooth muscle and CHRM3-mediated bronchoconstriction. U0126 could rescue PM10 exposure-induced pathological changes in the bronchus. In conclusion, PM10 exposure can induce bronchial hyperresponsiveness in rats by upregulating CHRM3, and the ERK1/2 pathway may be involved in this process. These findings could reveal a potential therapeutic target for air pollution induced respiratory diseases.

A novel histone deacetylase inhibitor Se-SAHA attenuates isoproterenol-induced heart failure via antioxidative stress and autophagy inhibition.

Heart failure is associated with histone deacetylase (HDAC) regulation of gene expression, the inhibition of which is thought to be beneficial for heart failure therapy. Here, we explored the cardioprotective effects and underlying mechanism of a novel selenium-containing HDAC inhibitor, Se-SAHA, on isoproterenol (ISO)-induced heart failure. We found that pretreatment with Se-SAHA attenuated ISO-induced cardiac hypertrophy and fibrosis in neonatal rat ventricular myocytes (NRVMs). Se-SAHA significantly attenuated the generation of ISO-induced reactive oxygen species (ROS) and restored the expression levels of superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) in vitro. Furthermore, Se-SAHA pretreatment prevented the accumulation of autophagosomes. Se-SAHA reversed the high expression of HDAC1 and HDAC6 induced by ISO incubation. However, after the addition of the HDAC agonist, the effect of Se-SAHA on blocking autophagy was inhibited. Using ISO-induced mouse models, cardiac ventricular contractile dysfunction, hypertrophy, and fibrosis was reduced treated by Se-SAHA. In addition, Se-SAHA inhibited HDAC1 and HDAC6 overexpression in ISO-treated mice. Se-SAHA treatment significantly increased the activity of SOD2 and improved the ability to eliminate free radicals. Se-SAHA hindered the excessive levels of the microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin-1 in heart failure mice. Collectively, our results indicate that Se-SAHA exerts cardio-protection against ISO-induced heart failure via antioxidative stress and autophagy inhibition.