NOP2 facilitates EZH2-mediated epithelial-mesenchymal transition by enhancing EZH2 mRNA stability via m5C methylation in lung cancer progression.

NOP2, a member of the NOL1/NOP2/SUN domain (NSUN) family, is responsible for catalyzing the posttranscriptional modification of RNA through 5-methylcytosine (m5C). Dysregulation of m5C modification has been linked to the pathogenesis of various malignant tumors. Herein, we investigated the expression of NOP2 in lung adenocarcinoma (LUAD) tissues and cells, and found that it was significantly upregulated. Moreover, lentivirus-mediated overexpression of NOP2 in vitro resulted in enhanced migration and invasion capabilities of lung cancer cells, while in vivo experiments demonstrated its ability to promote the growth and metastasis of xenograft tumors. In contrast, knockdown of NOP2 effectively inhibited the growth and metastasis of lung cancer cells. RNA-sequencing was conducted to ascertain the downstream targets of NOP2, and the findings revealed a significant upregulation in EZH2 mRNA expression upon overexpression of NOP2. Subsequent validation experiments demonstrated that NOP2 exerted an m5C-dependent influence on the stability of EZH2 mRNA. Additionally, our investigations revealed a co-regulatory relationship between NOP2 and the m5C reader protein ALYREF in modulating the stability of EZH2 mRNA. Notably, the NOP2/EZH2 axis facilitated the malignant phenotype of lung cancer cells by inducing epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Mechanistically, ChIP analysis proved that EZH2 counteracted the impact of NOP2 on the occupancy capacity of EZH2 and H3K27me3 in the promoter regions of E-cadherin, a gene crucial for regulating EMT. In a word, our research highlights the significant role of NOP2 in LUAD and offers novel mechanistic insights into the NOP2/ALYREF/EZH2 axis, which holds promise as a potential target for lung cancer therapy.

RNA methylation-related inhibitors: Biological basis and therapeutic potential for cancer therapy.

RNA methylation is widespread in nature. Abnormal expression of proteins associated with RNA methylation is strongly associated with a number of human diseases including cancer. Increasing evidence suggests that targeting RNA methylation holds promise for cancer treatment. This review specifically describes several common RNA modifications, such as the relatively well-studied N6-methyladenosine, as well as 5-methylcytosine and pseudouridine (Ψ). The regulatory factors involved in these modifications and their roles in RNA are also comprehensively discussed. We summarise the diverse regulatory functions of these modifications across different types of RNAs. Furthermore, we elucidate the structural characteristics of these modifications along with the development of specific inhibitors targeting them. Additionally, recent advancements in small molecule inhibitors targeting RNA modifications are presented to underscore their immense potential and clinical significance in enhancing therapeutic efficacy against cancer. KEY POINTS: In this paper, several important types of RNA modifications and their related regulatory factors are systematically summarised. Several regulatory factors related to RNA modification types were associated with cancer progression, and their relationships with cancer cell migration, invasion, drug resistance and immune environment were summarised. In this paper, the inhibitors targeting different regulators that have been proposed in recent studies are summarised in detail, which is of great significance for the development of RNA modification regulators and cancer treatment in the future.

Elimination of Acrolein by Disodium 5'-Guanylate or Disodium 5'-Inosinate at High Temperature and Its Application in Roasted Pork Patty.

Acrolein (ACR) is a highly active, simple unsaturated aldehyde found in various high-temperature processed foods. Its long-term accumulation in the human body increases the risk of chronic diseases. Animal and plant foodstuffs are rich in disodium 5'-guanylate (GMP) and disodium 5'-inosinate (IMP), which are authorized flavor enhancers. Herein, we used liquid chromatography with tandem mass spectrometry to explore the reaction-active kinetics and pathway of the interaction between GMP/IMP and ACR and validated it in roasted pork patties. Our results suggested that GMP and IMP could efficiently eliminate ACR by forming ACR adducts (GMP-ACR, IMP-ACR). In addition, IMP exhibited a higher reaction rate, whereas GMP had a good trapping capacity at a later stage. As carriers of GMP and IMP, dried mushrooms and shrimp exhibited an effective ACR-trapping ability in the ACR model and roasted pork patty individually and in combination. Adding 10% of dried mushroom or shrimp alone or 5% of dried mushroom and shrimp in combination eliminated up to 53.9%, 55.8%, and 55.2% ACR in a roasted pork patty, respectively. This study proposed a novel strategy to eliminate the generation of ACR in roasted pork patties by adding foodstuffs rich in GMP and IMP.

Efficacy and safety of iodized lecithin tablets versus spironolactone in alleviating central serous retinopathy among Chinese patients with uncontrolled diabetes.

To compare the effectiveness and safety of spironolactone versus lecithin-bound iodine in patients with central serous retinopathy (CSR). Chinese diabetes patients aged>18 years with CSR with persistent increased level of subretinal fluid (SRF) were enrolled. Subjects were randomized to receive either oral lecithin-bound iodine (390µg/kg/day) or oral spironolactone (50mg/day) for 6 months. A total of 200 patients were randomized and completed the study. Compared to spironolactone group, patients treated with lecithin-bound iodine had greater proportion of eye with complete resolution (87% vs 81%, p>0.005). Higher improvement in height of SRF was observed in lecithin-bound iodine-treated patients as compared with Spironolactone-treated patients (91.2[87.5] vs 142.5 [121.1]; p>0.005). However, no statistically significant difference was observed on none of comparisons. Compared to Spironolactone, the patients treated with lecithin-bound iodine had greater improvement in lesion size, central macular thickness and best-corrected visual acuity. However, no statistically significant difference was observed in any of parameter assessed. (p>0.005). The results of the present study suggested that the lecithin-bound iodine was found more effective (nnumerically) than spironolactone in Chinese diabetes patients with CSR.

Effects of hesperidin combined with synephrine on the capture of acrolein in a mouse model, or in humans by citrus consumption.

Acrolein (ACR) is a highly reactive α,ß-unsaturated aldehyde that plays a key role in the pathogenesis of human diseases, such as atherosclerosis and pulmonary, cardiovascular, and neurodegenerative disorders. We investigated the capture capacity of hesperidin (HES) and synephrine (SYN) on ACR by individual and combined means in vitro, in vivo (utilizing a mouse model), and via a human study. After proving that HES and SYN could efficiently capture ACR by generating ACR adducts in vitro, we further detected the adducts of SYN-2ACR, HES-ACR-1, and hesperetin (HESP)-ACR in mouse urine by ultraperformance liquid chromatography-tandem mass spectrometry. Quantitative assays revealed that adduct formation occurred in a dose-dependent manner, and that there was a synergistic effect of HES and SYN on capturing ACR in vivo. Moreover, quantitative analysis suggested that SYN-2ACR, HES-ACR-1, and HESP-ACR were formed and excreted through the urine of healthy volunteers consuming citrus. The maximum excretions of SYN-2ACR, HES-ACR-1, and HESP-ACR were at 2-4, 8-10, and 10-12 h, respectively, after dosing. Our findings propose a novel strategy for eliminating ACR from the human body via the simultaneous consumption of a flavonoid and an alkaloid.

Tree peony transcription factor PrWRI1 enhances seed oil accumulation.

BACKGROUND: WRINKLED1 (WRI1) encodes a transcription factor, belonging to the APETALA2 (AP2) family, and plays a key role in regulating plant oil biosynthesis. As a newly woody oil crop, tree peony (Paeonia rockii) was notable for the abundant unsaturated fatty acids in its seed oil. However, the role of WRI1 during the accumulation of P. rockii seeds oil remains largely unknown. RESULTS: In this study, a new member of the WRI1 family was isolated from P. rockii and was named PrWRI1. The ORF of PrWRI1 consisted of 1269 nucleotides, encoding a putative protein of 422 amino acids, and was highly expressed in immature seeds. Subcellular localization analysis in onion inner epidermal cells showed that PrWRI1 was located at the nucleolus. Ectopic overexpression of PrWRI1 could significantly increase the total fatty acid content in Nicotiana benthamiana leaf tissue and even PUFAs in transgenic Arabidopsis thaliana seeds. Furthermore, the transcript levels of most genes related to fatty acids (FA) synthesis and triacylglycerol (TAG) assembly were also up-regulated in transgenic Arabidopsis seeds. CONCLUSIONS: Together, PrWRI1 could push carbon flow to FA biosynthesis and further enhance the TAG amount in seeds with a high proportion of PUFAs.

SmCIP7, a COP1 interactive protein, positively regulates anthocyanin accumulation and fruit size in eggplant.

In higher plants, COP1 (Constitutively Photomorphogenic 1) acts as a central regulator of light-signaling networks and globally conditions the target proteins via the ubiquitin-proteasome pathway. However, the function of COP1-interacting proteins in light-regulated fruit coloration and development remains unknown in Solanaceous plants. Here, a COP1-interacting protein-encoding gene, SmCIP7, expressed specifically in the eggplant (Solanum melongena L.) fruit, was isolated. Gene-specific silencing of SmCIP7 using RNA interference (RNAi) significantly altered fruit coloration, fruit size, flesh browning, and seed yield. SmCIP7-RNAi fruits showed evident repression of the accumulation of anthocyanins and chlorophyll, indicating functional similarities between SmCIP7 and AtCIP7. However, the reduced fruit size and seed yield indicated SmCIP7 had evolved a distinctly new function. With the comprehensive application of HPLC-MS, RNA-seq, qRT-PCR, Y2H, BiFC, LCI, and dual-luciferase reporter system (DLR™), it was found that SmCIP7, a COP1 interactive protein in light signaling promoted anthocyanin accumulation, probably by regulating the transcription of SmTT8. Additionally, the drastic up-regulation of SmYABBY1, a homologous gene of SlFAS, might account for the strongly retarded fruit growth in SmCIP7-RNAi eggplant. Altogether, this study proved that SmCIP7 is an essential regulatory gene to modulate fruit coloration and development, serving as a key gene locus in eggplant molecular breeding.

Repurposed pizotifen malate targeting NRF2 exhibits anti-tumor activity through inducing ferroptosis in esophageal squamous cell carcinoma.

Targeted therapy attempts are needed to enhance esophageal squamous cell carcinoma (ESCC) patients' overall survival and satisfaction of life. Nuclear factor erythroid 2-related factor 2 (NRF2), as a high-confidence cancer driver gene, controls the antioxidant response, metabolic balance and redox homeostasis in cancer and is regarded as a potent molecular target for cancer treatment. Here, we attempted to find a new NRF2 inhibitor and study the underlying molecular mechanism in ESCC. We found that up-regulated NRF2 protein was negatively correlated with patient prognosis and promoted tumor proliferation in ESCC. Moreover, Pizotifen malate (PZM), a FDA-approved medication, bound to the Neh1 domain of NRF2 and prevented NRF2 protein binding to the ARE motif of target genes, suppressing transcription activity of NRF2. PZM treatment suppressed tumor development in ESCC PDX model by inducing ferroptosis via down-regulating the transcription of GPX4, GCLC, ME1 and G6PD. Our study illustrates that the over expression of NRF2 indicates poor prognosis and promotes tumor proliferation in ESCC. PZM, as a novel NRF2 inhibitor, inhibits the tumor growth by inducing ferroptosis and elucidates a potent NRF2-based therapy strategy for patients with ESCC.

Developmental Differences between Anthers of Diploid and Autotetraploid Rice at Meiosis.

Newly synthetic autotetraploid rice shows lower pollen fertility and seed setting rate relative to diploid rice, which hinders its domestication and breeding. In this study, cytological analysis showed that at meiosis I stage, an unbalanced segregation of homologous chromosomes, occurred as well as an early degeneration of tapetal cells in autotetraploid rice. We identified 941 differentially expressed proteins (DEPs) in anthers (meiosis I), including 489 upregulated and 452 downregulated proteins. The DEPs identified were related to post-translational modifications such as protein ubiquitination. These modifications are related to chromatin remodeling and homologous recombination abnormalities during meiosis. In addition, proteins related to the pentose phosphate pathway (BGIOSGA016558, BGIOSGA022166, and BGIOSGA028743) were downregulated. This may be related to the failure of autotetraploid rice to provide the energy needed for cell development after polyploidization, which then ultimately leads to the early degradation of the tapetum. Moreover, we also found that proteins (BGIOSGA017346 and BGIOSGA027368) related to glutenin degradation were upregulated, indicating that a large loss of glutenin cannot provide nutrition for the development of tapetum, resulting in early degradation of tapetum. Taken together, these evidences may help to understand the differences in anther development between diploid and autotetraploid rice during meiosis.

Food additive octyl gallate eliminates acrolein and inhibits bacterial growth in oil-rich food.

Acrolein (ACR) is predominantly generated from oil-rich food during thermos- processing. Accumulation of ACR in vivo through food consumption has been associated with an increased risk of developing chronic diseases. Here, we investigated the inhibitory effect of octyl gallate (OG), a new food additive tolerant to high-temperature, alkaline and fat-soluble saturations, on the generation of ACR in OG-ACR, oil-Rancimat models, and real-world frying. Our results demonstrate that approximately 80% and 60% of ACR was eliminated by OG in the two models, respectively, and OG-ACR was detected in the deep-frying process using LC-MS/MS. The reaction pathways were clarified by synthesis and OG-ACR and OG-2ACR adduct structural elucidation. Our work reveals that the antibacterial activity of OG-ACR against Escherichia coli (gram-negative) was four times higher than that of OG. Thus, OG can be developed as a promising novel ACR scavenger for high-temperature food processing and an antibacterial agent in food storage.

Integrated Transcriptomic and Metabolomic Analyses Reveal the Mechanisms Underlying Anthocyanin Coloration and Aroma Formation in Purple Fennel.

The color and aroma are the significant traits of vegetables and fruits, but the metabolic and molecular mechanisms underlying anthocyanin accumulation and aroma formation remain almost unknown in fennel (Anethum foeniculum L.), which is a crucial vegetable crop and grown widely for aromatic leaves and bulbs. Here, ten major anthocyanins identified and quantified by ultra-high performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) were mainly responsible for the coloration of purple fennel leaf. With the application of GC-MS, it was found that the reduced volatile phenylpropanoids including isoeugenol, trans-isoeugenol, and apiol chiefly account for the characteristic aroma changes of the purple fennel. Moreover, the characteristic anthocyanin coloration and aroma formation in purple fennel were systematically studied with the integrated transcriptomics and metabolomics. The critical genes associated with the biosynthesis and regulation of anthocyanins and volatile phenylpropanoids were isolated and studied carefully in transiently transfected tobacco cells and transgenic tomato plants. Together with the results of UHPLC-Q-Orbitrap HRMS, RT-qPCR, and yeast two hybrid (Y2H), it is proved that the metabolic flux redirection of phenylpropanoid pathway primarily regulated by a functional MYB-bHLH-WD40 complex consisting of AfTT8, AfMYB7, and AfTTG1 accounts for the characteristic anthocyanin coloration and aroma formation in purple fennel leaf. The systematic understanding of the anthocyanin accumulation and aroma formation will assist in the improvement of fennel resource utilization and breeding.

Association between anxiety symptoms and atrial fibrillation in a community cohort of Chinese older adults: a case-control study.

BACKGROUND: The association between anxiety and atrial fibrillation (AF) remains unclear. Moreover, this association has rarely been studied in Chinese individuals aged 60 years or older. This study investigated the association between anxiety and AF in a community-based case-control study of older adult residents in urban China. METHODS: The cases and controls were from a community-based study conducted in the Jingansi community in Shanghai, China, between January 2010 and December 2012. A total of 3622 residents aged 60 years or older without severe vision, hearing, or speaking impairments were eligible to participate in the physical examinations and questionnaire survey. AF was assessed based on a previous physician's diagnosis, electrocardiogram, ambulatory electrocardiogram, or echocardiogram. Anxiety was evaluated using the Zung Self-Rating Anxiety Scale (ZSAS). Using the AF group as a reference, the control group consisted of randomly selected age- and sex-matched individuals in a 1:5 ratio (case:control = 1:5). The association between anxiety and AF in the AF group and the multifactor-matched control group was explored using logistic regression. RESULTS: In the AF and control groups, after adjusting for a history of coronary heart disease, valvular heart disease, hypertension, stroke, hyperlipidemia, and diabetes, as well as depression score, ZSAS scores (odds ratio 1.07; 95% confidence interval 1.02-1.12; p = 0.003), and anxiety symptoms (odds ratio 3.94; 95% confidence interval 1.06-14.70; p = 0.041) were associated with AF. CONCLUSIONS: Anxiety symptoms were associated with AF in a Chinese older population. This suggests that older adults who have anxiety symptoms may need psychological intervention or treatment in daily life and care.

Comparative Transcriptome Analysis of the Accumulation of Anthocyanins Revealed the Underlying Metabolic and Molecular Mechanisms of Purple Pod Coloration in Okra (Abelmoschus esculentus L.).

Color is an essential agronomic trait and the consumption of high anthocyanin containing vegetables in daily diet does provide benefits to human health, but the mechanisms on anthocyanin accumulation in tender pods of okra (Abelmoschus esculentus L.) were totally unknown. In this study, a wide characterization and quantitation of anthocyanins and flavonols in tender pods of 15 okra varieties were performed by UHPLC-Q-Orbitrap HRMS for the first time. Two major anthocyanins (delphinidin 3-O-sambubioside and cyanidin 3-O-sambubioside) and six kinds of flavonol glycosides (most are quercetin-based) were identified and quantified. The coloration of the purple okra pod mainly arises from the accumulation of both delphinidin 3-O-sambubioside and cyanidin 3-O-sambubioside in most of purple varieties (Hong Yu, Bowling Red and Burgundy), except Jing Orange. The significant differences in the compositions and contents of anthocyanins are responsible for the pod color ranging from brick-red to purplish-red among the various okra cultivars. Furthermore, four representative okra cultivars exhibiting obvious differences in anthocyanin accumulation were further analyzed with transcriptome and more than 4000 conserved differentially expressed genes were identified across the three compared groups (B vs. BR, B vs. HY and B vs. JO). Based on the comprehensive analysis of transcriptomic data, it was indicated that MBW complex consisting of AeMYB114, AeTT8, and AeTTG1 and other transcriptional factors coordinately regulate the accumulation of anthocyanins via the transcriptional regulation of structural genes. Moreover, four independent working models explaining the diversities of anthocyanin pigmentation in okra pods were also proposed. Altogether, these results improved our understanding on anthocyanin accumulation in okra pods, and provided strong supports for the development of okra pod as a functional food in the future.

A link between protein acetylation and mitochondrial dynamics under energy metabolism: A comprehensive overview.

Cells adjust mitochondrial morphologies to coordinate between the cellular demand for energy and the availability of resources. Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. Fission and fusion are dynamic and reversible processes that depend on the coordination of a number of proteins and are primarily regulated by posttranslational modifications. In the mitochondria, more than 20% of proteins are acetylated in proteomic surveys, partly involved in the dynamic regulation of mitochondrial fusion and fission. This article focuses on the molecular mechanism of the mitochondrial dynamics of fusion and fission, and summarizes the related mechanisms and targets of mitochondrial protein acetylation to regulate the mitochondrial dynamics of fusion and fission in energy metabolism.

Protein acetylation: a novel modus of obesity regulation.

Obesity is a chronic epidemic disease worldwide which has become one of the important public health issues. It is a process that excessive accumulation of adipose tissue caused by long-term energy intake exceeding energy expenditure. So far, the prevention and treatment strategies of obesity on individuals and population have not been successful in the long term. Acetylation is one of the most common ways of protein post-translational modification (PTM). It exists on thousands of non-histone proteins in almost every cell chamber. It has many influences on protein levels and metabolome levels, which is involved in a variety of metabolic reactions, including sugar metabolism, tricarboxylic acid cycle, and fatty acid metabolism, which are closely related to biological activities. Studies have shown that protein acetylation levels are dynamically regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). Protein acetylation modifies protein-protein and protein-DNA interactions and regulates the activity of enzymes or cytokines which is related to obesity in order to participate in the occurrence and treatment of obesity-related metabolic diseases. Therefore, we speculated that acetylation was likely to become effective means of controlling obesity in the future. In consequence, this review focuses on the mechanisms of protein acetylation controlled obesity, to provide theoretical basis for controlling obesity and curing obesity-related diseases, which is a significance for regulating obesity in the future. This review will focus on the role of protein acetylation in controlling obesity.

ER stress-induced adipocytes secrete-aldo-keto reductase 1B7-containing exosomes that cause nonalcoholic steatohepatitis in mice.

Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent liver disease linked to obesity and associated complications. Endoplasmic reticulum (ER) stress provokes dysfunction in lipid metabolism, which often leads to a progression of obesity-induced hepatic steatosis to NASH. However, the underlying mechanisms in which ER stress in adipose tissue induces hepatic pathology remain elusive. Here, we used male C57BL/6J mice to develop an animal model of NASH induced by a high fat (HFD) diet and methionine- and choline-deficient (MCD) diets. Using a gene-silencing approach with a recombinant lentiviral vector and extensive LC-MS/MS-based proteomics and lipidomics, we demonstrate that the ER stress-induced adipocyte-secreted exosome (ATEx) orchestrates lipid dynamics in the liver. We also noted that ATEx causes hepatic steatosis, inflammation, and fibrosis that lead to NASH through initial accumulation of glycerol and triglycerides in hepatocytes. We also determined that aldo-keto-reductase 1B7 (Akr1b7), a key mediator in liver lipid metabolism, is involved in ATEx-mediated NASH induction. Of note, Akr1b7 deficiency in ER stress-induced ATEx strongly protected the murine liver against HFD and MCD-induced NASH. Our results indicated that ER stress-induced, adipocyte-secreted ATEx triggers NASH by delivering exosomal AKR1B7 to, and elevating glycerol level, in hepatocytes. These findings suggest potential therapeutic strategie that target ATEx to prevent or manage obesity-induced NASH.

Concise Review: The Regulatory Mechanism of Lysine Acetylation in Mesenchymal Stem Cell Differentiation.

Nowadays, the use of MSCs has attracted considerable attention in the global science and technology field, with the self-renewal and multidirectional differentiation potential for diabetes, obesity treatment, bone repair, nerve repair, myocardial repair, and so on. Epigenetics plays an important role in the regulation of mesenchymal stem cell differentiation, which has become a research hotspot in the medical field. This review focuses on the role of lysine acetylation modification on the determination of MSC differentiation direction. During this progress, the recruitment of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) is the crux of transcriptional mechanisms in the dynamic regulation of key genes controlling MSC multidirectional differentiation.

Effects of nitrogen on interspecific competition between two cell-size cyanobacteria: Microcystis aeruginosa and Synechococcus sp.

Micro-cyanobacteria and pico-cyanobacteria coexist in many lakes throughout the world. Their distinct cell sizes and nutrient utilization strategies may lead to dominance of one over the other at varying nutrient levels. In this study, Microcystis aeruginosa and Synechococcus sp. were chosen as representative organisms of micro- and pico-cyanobacteria, respectively. A series of nitrate and ammonia conditions (0.02, 0.1, 0.5, and 2.5 mg N L-1) were designed in mono- or co-cultured systems, respectively. Growth rates of the two species were calculated and fitted by the Monod and Logistic equations. Furthermore, the interspecific competition was analyzed using the Lotka-Volterra model. In mono-cultures, the two cyanobacteria displayed faster growth rates in ammonia than in nitrate. Meanwhile, Synechococcus sp. showed faster growth rates compared to M. aeruginosa in lower N groups (≤ 0.5 mg N L-1). However, in the highest nitrate treatment (2.5 mg N L-1), M. aeruginosa achieved much higher biomass and faster growth rates than Synechococcus sp.. In co-cultures, Synechococcus sp. dominated in the lowest N treatment (0.02 mg N L-1), but M. aeruginosa dominated under the highest nitrate condition (2.5 mg N L-1). Based on the analysis of Raman spectra of living cells in mono-cultures, nitrate (2.5 mg N L-1) upgraded the pigmentary contents of M. aeruginosa better than ammonia (2.5 mg N L-1), but nitrogen in different forms showed little effects on the pigments of Synechococcus sp.. Findings from this study can provide valuable information to predict cyanobacterial community succession and aquatic ecosystem stability.

Nuclear receptor corepressor 1 represses cardiac hypertrophy.

The function of nuclear receptor corepressor 1 (NCoR1) in cardiomyocytes is unclear, and its physiological and pathological implications are unknown. Here, we found that cardiomyocyte-specific NCoR1 knockout (CMNKO) mice manifested cardiac hypertrophy at baseline and had more severe cardiac hypertrophy and dysfunction after pressure overload. Knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine-induced cardiomyocyte hypertrophy. Mechanistic studies revealed that myocyte enhancer factor 2a (MEF2a) and MEF2d mediated the effects of NCoR1 on cardiomyocyte hypertrophy. The receptor interaction domains (RIDs) of NCoR1 interacted with MEF2a to repress its transcriptional activity. Furthermore, NCoR1 formed a complex with MEF2a and class IIa histone deacetylases (HDACs) to suppress hypertrophy-related genes. Finally, overexpression of RIDs of NCoR1 in the heart attenuated cardiac hypertrophy and dysfunction induced by pressure overload. In conclusion, NCoR1 cooperates with MEF2 and HDACs to repress cardiac hypertrophy. Targeting NCoR1 and the MEF2/HDACs complex may be an attractive therapeutic strategy to tackle pathological cardiac hypertrophy.