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Cancer constitutes a multifaceted ailment characterized by the dysregulation of numerous genes and pathways. Among these, LIM domain only 7 (LMO7) has emerged as a significant player in various cancer types, garnering substantial attention for its involvement in tumorigenesis and cancer progression. This review endeavors to furnish a comprehensive discourse on the functional intricacies and mechanisms of LMO7 in cancer, with a particular emphasis on its potential as both a therapeutic target and prognostic indicator. It delves into the molecular attributes of LMO7, its implications in cancer etiology and the underlying mechanisms propelling its oncogenic properties. Furthermore, it underscores the extant challenges and forthcoming prospects in targeting LMO7 for combating cancer.
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Proteínas con Dominio LIM , Neoplasias , Factores de Transcripción , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Proteínas con Dominio LIM/metabolismo , Proteínas con Dominio LIM/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación Neoplásica de la Expresión Génica , Pronóstico , Carcinogénesis/genética , Terapia Molecular Dirigida/métodosRESUMEN
Circadian rhythms of approximately 24 h have emerged as important modulators of the immune system. These oscillations are important for mounting short-term, innate immune responses, but surprisingly also long-term, adaptive immune responses. Recent data indicate that they play a central role in antitumor immunity, in both mice and humans. In this review, we discuss the evolving literature on circadian antitumor immune responses and the underlying mechanisms that control them. We further provide an overview of circadian treatment regimens-chrono-immunotherapies-that harness time-of-day differences in immunity for optimal efficacy. Our aim is to provide an overview for researchers and clinicians alike, for a better understanding of the circadian immune system and how to best harness it for chronotherapeutic interventions. This knowledge is important for a better understanding of immune responses per se and could revolutionize the way we approach the treatment of cancer and a range of other diseases, ultimately improving clinical practice.
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Ritmo Circadiano , Neoplasias , Humanos , Ritmo Circadiano/inmunología , Animales , Neoplasias/inmunología , Neoplasias/terapia , Inmunoterapia/métodos , Inmunidad Innata , Inmunidad AdaptativaRESUMEN
BACKGROUND: Recent experimental studies of neuroinflammation in glaucoma pointed to cFLIP as a molecular switch for cell fate decisions, mainly regulating cell type-specific caspase-8 functions in cell death and inflammation. This study aimed to determine the importance of cFLIP for regulating astroglia-driven neuroinflammation in experimental glaucoma by analyzing the outcomes of astroglia-targeted transgenic deletion of cFLIP or cFLIPL. METHODS: Glaucoma was modeled by anterior chamber microbead injections to induce ocular hypertension in mouse lines with or without conditional deletion of cFLIP or cFLIPL in astroglia. Morphological analysis of astroglia responses assessed quantitative parameters in retinal whole mounts immunolabeled for GFAP and inflammatory molecules or assayed for TUNEL. The molecular analysis included 36-plexed immunoassays of the retina and optic nerve cytokines and chemokines, NanoString-based profiling of inflammation-related gene expression, and Western blot analysis of selected proteins in freshly isolated samples of astroglia. RESULTS: Immunoassays and immunolabeling of retina and optic nerve tissues presented reduced production of various proinflammatory cytokines, including TNFα, in GFAP/cFLIP and GFAP/cFLIPL relative to controls at 12 weeks of ocular hypertension with no detectable alteration in TUNEL. Besides presenting a similar trend of the proinflammatory versus anti-inflammatory molecules displayed by immunoassays, NanoString-based molecular profiling detected downregulated NF-κB/RelA and upregulated RelB expression of astroglia in ocular hypertensive samples of GFAP/cFLIP compared to ocular hypertensive controls. Analysis of protein expression also revealed decreased phospho-RelA and increased phospho-RelB in parallel with an increase in caspase-8 cleavage products. CONCLUSIONS: A prominent response limiting neuroinflammation in ocular hypertensive eyes with cFLIP-deletion in astroglia values the role of cFLIP in the molecular regulation of glia-driven neuroinflammation during glaucomatous neurodegeneration. The molecular responses accompanying the lessening of neurodegenerative inflammation also seem to maintain astroglia survival despite increased caspase-8 cleavage with cFLIP deletion. A transcriptional autoregulatory response, dampening RelA but boosting RelB for selective expression of NF-κB target genes, might reinforce cell survival in cFLIP-deleted astroglia.
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Astrocitos , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Glaucoma , Enfermedades Neuroinflamatorias , Animales , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Ratones , Astrocitos/metabolismo , Astrocitos/patología , Glaucoma/metabolismo , Glaucoma/patología , Glaucoma/genética , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Ratones Transgénicos , Modelos Animales de Enfermedad , Citocinas/metabolismo , Retina/metabolismo , Retina/patología , Ratones Endogámicos C57BL , Nervio Óptico/patología , Nervio Óptico/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismoRESUMEN
The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.
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Linfocitos T CD8-positivos , Inmunoterapia , Linfocitos Infiltrantes de Tumor , Ratones Endogámicos C57BL , Microambiente Tumoral , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Relojes Circadianos , Ritmo Circadiano , Células Endoteliales/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Melanoma/terapia , Melanoma/patología , Microambiente Tumoral/inmunologíaRESUMEN
Circadian rhythms exert a profound impact on most aspects of mammalian physiology, including the immune and cardiovascular systems. Leukocytes engage in time-of-day-dependent interactions with the vasculature, facilitating the emigration to and the immune surveillance of tissues. This review provides an overview of circadian control of immune-vascular interactions in both the steady state and cardiovascular diseases such as atherosclerosis and infarction. Circadian rhythms impact both the immune and vascular facets of these interactions, primarily through the regulation of chemoattractant and adhesion molecules on immune and endothelial cells. Misaligned light conditions disrupt this rhythm, generally exacerbating atherosclerosis and infarction. In cardiovascular diseases, distinct circadian clock genes, while functioning as part of an integrated circadian system, can have proinflammatory or anti-inflammatory effects on these immune-vascular interactions. Here, we discuss the mechanisms and relevance of circadian rhythms in vascular immunopathologies.
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Aterosclerosis , Enfermedades Cardiovasculares , Relojes Circadianos , Animales , Aterosclerosis/genética , Relojes Circadianos/genética , Ritmo Circadiano/genética , Células Endoteliales , Infarto , MamíferosRESUMEN
Ferroptosis is a newly recognized type of regulated cell death that is characterized by the accumulation of iron and lipid peroxides in cells. Studies have shown that ferroptosis plays a significant role in the pathogenesis of various diseases, including cardiovascular diseases. In cardiovascular disease, ferroptosis is associated with ischemia-reperfusion injury, myocardial infarction, heart failure, and atherosclerosis. The molecular mechanisms underlying ferroptosis include the iron-dependent accumulation of lipid peroxidation products, glutathione depletion, and dysregulation of lipid metabolism, among others. This review aims to summarize the current knowledge of the molecular mechanisms of ferroptosis in cardiovascular disease and discuss the potential therapeutic strategies targeting ferroptosis as a treatment for cardiovascular disease.
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Four 2-hydroxy-N-alkyl-N-phenyl-nicotinamides (1-4) were synthesized, and their crystal structures were analyzed to investigate the effect of substitution on their crystal packing of N-phenyl-2-hydroxynicotinanilides. In these compounds, substituents were introduced on the amide N, leading to a peptoid-like structure. One solvent-free form and two hydrates were harvested for compound 1, and one anhydrous form and one hydrate were obtained for compound 2. Polymorphism was observed in compounds 3 and 4. The molecules were found to be in the keto form rather than the enol tautomer. Because of steric effects, the molecules took on an E configuration, leading to a hairpin-like geometry. A lactam-lactam dimer synthon was formed in all solvent-free structures, and a tetramer motif was observed for the first time. Dehydration of the two hydrates of 1 and the hydrate of 2 led to their respective solvent-free form. Phase transition between the polymorphs was revealed in compound 3. Theoretical calculations, including conformational energy evaluation, hydrate forming propensity assessment, and lattice energy appraisal, were performed to provide a reasonable explanation for the keto tautomer and the formation of the hydrates of compound 1.
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Background: Obesity and overweight are common in young patients with major depressive disorder (MDD). However, the prevalence and associated clinical factors of obesity/overweight in young first-episode and drug-naïve (FEDN) MDD patients are rarely reported in China. Methods: A cross-sectional study of 917 young patients (aged 18-35 years) with FEDN MDD was performed. Demographic and clinical data were collected. Depression, anxiety, and psychotic symptoms were assessed using the Hamilton Depression Scale (HAMD), the Hamilton Anxiety Scale (HAMA), and the Positive and Negative Syndrome Scale (PANSS) positive subscale, respectively. Results: Among the young MDD patients, the prevalence of obesity and overweight was 4.14 and 52.89%, respectively. Compared to normal-weight patients, overweight patients were older, had a greater age of onset, and had higher TSH and TG levels. Male MDD patients had a higher risk of obesity than female patients. Compared to obese patients, normal-weight and overweight patients had significantly lower HAMD scores, TC levels, and rates of TSH abnormalities. Logistic regression analysis showed that age, age of onset, and sex were independently associated with obesity, and TSH was independently associated with both obesity and overweight, in young MDD patients. Conclusion: Our findings suggest a high prevalence of overweight and obesity in young FEDN MDD patients. Several demographic and clinical variables are independently associated with overweight/obesity in these young MDD patients.
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Alkaline phosphatase (ALP) is a group of enzymes that catalyze hydrolysis of phosphate esters at an alkaline pH, resulting in the generation of inorganic phosphate. These enzymes are widely distributed, and their activity is found in various tissues including bone, liver, intestine, and placenta. However, abnormalities in ALP expression and activity have been observed in certain types of cancer. In some cases, elevated serum levels of ALP are observed in patients with liver and bone metastasis. In other cases, increased levels of ALP have been observed in patients with pancreatic and lung cancer. On the other hand, low expression of ALP has also been associated with poor prognosis in patients with certain types of tumors, including colorectal cancer (CRC), breast cancer, and non-small cell lung cancer (NSCLC). In these cases, low ALP activity may be associated with decreased differentiation of cancer cells and increased cancer cell proliferation. Overall, the role of ALP in cancer is complex and context-dependent. This article reviews application progress of ALP in cancer, and we hypothesize that ALP might be a potential tumor biomarker, combined detection of aspartate aminotransferase (AST)/alanine aminotransferase (ALT), bone-specific alkaline phosphatase (BSAP), carbohydrate antigen 19-9 (CA 19-9), lactate dehydrogenase (LDH) and ALP isozymes levels can be used for more accurate diagnosis of a particular tumor. Further research is needed to better understand the mechanisms underlying ALP dysregulation in cancer and to identify potential therapeutic targets.
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To investigate the polymorphism in 4-phenylamino-benzoic acids (4-PABAs) in general, and the effect on the polymorphism of these compounds exerted by substitution in particular, a series of 4-PABAs (1-8) varying in the substitution position and pattern were synthesized, and their polymorphic behavior was investigated for the first time. A relatively comprehensive polymorph screening led to the discovery of two forms, one solvent-free and the other solvate, for compounds 1, 3 and 8, and one form for the other compounds. The crystal structures were determined by single-crystal XRD. All the 4-PABAs in the crystal structures are highly twisted, and all the solvent-free crystals are based on the conventional acid-acid dimer motif, except for 2, which has a rarely observed acid-acid catemer motif. Two of the solvates (1-S and 8-S) have pyridine in the lattice while the other (3-S) has dichloromethane. The observation indicates that neither conformational flexibility or substitution alone nor the combination of both leads to polymorphism in these compounds, which is in dramatic contrast to the polymorphism of fenamic acids. The thermal properties of each system were investigated by differential scanning calorimetry and desolvation of the solvates was studied by thermogravimetric analysis. Hirshfeld surface analysis and molecular dynamics simulation were performed to study the mechanism of polymorphism and the intermolecular interactions contributing to the formation and stability of each crystal form.
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Anti-angiogenic therapies (AATs) are used to treat different types of cancers. However, their success is limited owing to insufficient efficacy and resistance. Recently, single-cell omics studies of tumour endothelial cells (TECs) have provided new mechanistic insight. Here, we overview the heterogeneity of human TECs of all tumour types studied to date, at the single-cell level. Notably, most human tumour types contain varying numbers but only a small population of angiogenic TECs, the presumed targets of AATs, possibly contributing to the limited efficacy of and resistance to AATs. In general, TECs are heterogeneous within and across all tumour types, but comparing TEC phenotypes across tumours is currently challenging, owing to the lack of a uniform nomenclature for endothelial cells and consistent single-cell analysis protocols, urgently raising the need for a more consistent approach. Nonetheless, across most tumour types, universal TEC markers (ACKR1, PLVAP and IGFBP3) can be identified. Besides angiogenesis, biological processes such as immunomodulation and extracellular matrix organization are among the most commonly predicted enriched signatures of TECs across different tumour types. Although angiogenesis and extracellular matrix targets have been considered for AAT (without the hoped success), the immunomodulatory properties of TECs have not been fully considered as a novel anticancer therapeutic approach. Therefore, we also discuss progress, limitations, solutions and novel targets for AAT development.
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Células Endoteliales , Neoplasias , Humanos , Neovascularización Patológica/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , FenotipoRESUMEN
BACKGROUND: LIM domain is considered to be important in mediating protein-protein interactions, and members of the LIM protein family can co-regulate tissue-specific gene expression by interacting with different transcription factors. However, its exact function in vivo remains unclear. Our study demonstrates that the LIM protein family member Lmpt may act as a cofactor that interacts with other transcription factors to regulate cellular functions. METHODS: In this study, we generated Lmpt knockdown Drosophila (Lmpt-KD) using the UAS-Gal4 system. We assessed the lifespan and motility of Lmpt-KD Drosophila and analyzed the expression of muscle-related and metabolism-related genes using qRT-PCR. Additionally, we utilized Western blot and Top-Flash luciferase reporter assay to evaluate the level of the Wnt signaling pathway. RESULTS: Our study revealed that knockdown of the Lmpt gene in Drosophila resulted in a shortened lifespan and reduced motility. We also observed a significant increase in oxidative free radicals in the fly gut. Furthermore, qRT-PCR analysis indicated that knockdown of Lmpt led to decreased expression of muscle-related and metabolism-related genes in Drosophila, suggesting that Lmpt plays a crucial role in maintaining muscle and metabolic functions. Finally, we found that reduction of Lmpt significantly upregulated the expression of Wnt signaling pathway proteins. CONCLUSION: Our results demonstrate that Lmpt is essential for motility and survival in Drosophila and acts as a repressor in Wnt signaling.
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Proteínas de Drosophila , Drosophila , Animales , Drosophila/genética , Vía de Señalización Wnt , Proteínas de Drosophila/genética , Proteína Wnt1/genética , Factores de Transcripción/genética , Músculos/metabolismoRESUMEN
Epididymitis is an epididymal inflammation that may lead to male infertility. Dendritic cells (DCs) and myeloid differentiation primary response gene 88 (Myd88) were associated with epididymitis in rodents. However, the functions of Myd88 on epididymal DCs remain unclear. This study investigated the role of Myd88 in DCs for epididymitis. The Myd88 signaling pathway, phenotypes of DC subsets, and cytokines were investigated in lipopolysaccharide (LPS)-induced epididymitis in mice. CRISPR-Cas9 was used to knockout Myd88 in bone-marrow-derived dendritic cells (BMDCs) and immortalized mouse epididymal (DC2) cell line. In the vivo experiments, levels of the proinflammatory cytokines IL-1α, IL-6, IL-17A, TNF-α, IL-1ß, MCP-1, and GM-CSF, mRNA for MyD88 related genes, and the percentages of monocyte-derived DCs (Mo-DCs) were significantly elevated in mice with epididymitis. In the vitro experiments, LPS significantly promoted the apoptosis of BMDCs. In addition, the concentration of inflammatory cytokines in BMDCs and DC2s were increased in the LPS group, while decreasing after the knockout of Myd88. These findings indicate that Myd88 on DCs is involved in the inflammation of epididymitis in mice, which may be a potential target for better strategies regarding the treatment of immunological male infertility.
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Epididimitis , Humanos , Masculino , Animales , Ratones , Epididimitis/metabolismo , Lipopolisacáridos/farmacología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Médula Ósea/metabolismo , Células Dendríticas , Transducción de Señal , Citocinas/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BLRESUMEN
Citrullus ecirrhosus, Citrullus rehmii, and Citrullus naudinianus are three important related wild species of watermelon in the genus Citrullus, and their morphological differences are clear, however, their chloroplast genome differences remain unknown. This study is the first to assemble, analyze, and publish the complete chloroplast genomes of C. ecirrhosus, C. rehmii, and C. naudinianus. A comparative analysis was then conducted among the complete chloroplast genomes of seven extant Citrullus species, and the results demonstrated that the average genome sizes of Citrullus is 157,005 bp, a total of 130-133 annotated genes were identified, including 8 rRNA, 37 tRNA and 85-88 protein-encoding genes. Their gene content, order, and genome structure were similar. However, noncoding regions were more divergent than coding regions, and rps16-trnQ was a hypervariable fragment. Thirty-four polymorphic SSRs, 1,271 SNPs and 234 INDELs were identified. Phylogenetic trees revealed a clear phylogenetic relationship of Citrullus species, and the developed molecular markers (SNPs and rps16-trnQ) could be used for taxonomy in Citrullus. Three genes (atpB, clpP1, and rpoC2) were identified to undergo selection and would promote the environmental adaptation of Citrullus.
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Citrullus , Genoma del Cloroplasto , Citrullus/genética , Filogenia , Cloroplastos/genética , Variación GenéticaRESUMEN
LIM domain protein 2, also known as LIM protein FHL2, is a member of the LIM-only family. Due to its LIM domain protein characteristics, FHL2 is capable of interacting with various proteins and plays a crucial role in regulating gene expression, cell growth, and signal transduction in muscle and cardiac tissue. In recent years, mounting evidence has indicated that the FHLs protein family is closely associated with the development and occurrence of human tumors. On the one hand, FHL2 acts as a tumor suppressor by down-regulating in tumor tissue and effectively inhibiting tumor development by limiting cell proliferation. On the other hand, FHL2 serves as an oncoprotein by up-regulating in tumor tissue and binding to multiple transcription factors to suppress cell apoptosis, stimulate cell proliferation and migration, and promote tumor progression. Therefore, FHL2 is considered a double-edged sword in tumors with independent and complex functions. This article reviews the role of FHL2 in tumor occurrence and development, discusses FHL2 interaction with other proteins and transcription factors, and its involvement in multiple cell signaling pathways. Finally, the clinical significance of FHL2 as a potential target in tumor therapy is examined.
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Neoplasias , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias/genética , Transducción de Señal , Proteínas con Dominio LIM , Proteínas con Homeodominio LIM/genética , Proteínas con Homeodominio LIM/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismoRESUMEN
Momordica cochinchinensis (Lour.) Spreng. is an important medicinal plant that is used to treat various diseases in South and Southeast Asia. In this study, the complete plastome of M. cochinchinensis was sequenced and found to exhibit a total length of 158,955 bp, with a large single copy (LSC) region of 87,924 bp and a small single copy (SSC) region of 18,479 bp, as well as with two inverted repeats (IRs) that were both 26,726 bp in length. In total, 129 genes were detected, comprising 86 protein-encoding genes, 8 ribosomal RNA (rRNA) genes, and 35 transfer RNA (tRNA) genes. Furthermore, the inferred phylogenetic tree confirmed that M. cochinchinensis belongs to the genus Momordica in the Cucurbitaceae family. The research results will be used for authenticating M. cochinchinensis plant materials and for analyzing the genetic diversity and phylogenetic relationships in Momordica.
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Establishing the absolute configuration of chiral active pharmaceutical ingredients (APIs) is of great importance. Single crystal X-ray diffraction (scXRD) has traditionally been the method of choice for such analysis, but scXRD requires the growth of large crystals, which can be challenging. Here, we present a method for determining absolute configuration that does not rely on the growth of large crystals. By examining microcrystals formed with chiral probes (small chiral compounds such as amino acids), absolute configuration can be unambiguously determined by microcrystal electron diffraction (MicroED). Our streamlined method employs three steps: (1) virtual screening to identify promising chiral probes, (2) experimental cocrystal screening and (3) structure determination by MicroED and absolute configuration assignment. We successfully applied this method to analyze two chiral API molecules currently on the market for which scXRD was not used to determine absolute configuration.
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Cardiomyopathy is a common disease of cardiac muscle that negatively affects cardiac function. HDAC3 commonly functions as corepressor by removing acetyl moieties from histone tails. However, a deacetylase-independent role of HDAC3 has also been described. Cardiac deletion of HDAC3 causes reduced cardiac contractility accompanied by lipid accumulation, but the molecular function of HDAC3 in cardiomyopathy remains unknown. We have used powerful genetic tools in Drosophila to investigate the enzymatic and nonenzymatic roles of HDAC3 in cardiomyopathy. Using the Drosophila heart model, we showed that cardiac-specific HDAC3 knockdown (KD) leads to prolonged systoles and reduced cardiac contractility. Immunohistochemistry revealed structural abnormalities characterized by myofiber disruption in HDAC3 KD hearts. Cardiac-specific HDAC3 KD showed increased levels of whole-body triglycerides and increased fibrosis. The introduction of deacetylase-dead HDAC3 mutant in HDAC3 KD background showed comparable results with wild-type HDAC3 in aspects of contractility and Pericardin deposition. However, deacetylase-dead HDAC3 mutants failed to improve triglyceride accumulation. Our data indicate that HDAC3 plays a deacetylase-independent role in maintaining cardiac contractility and preventing Pericardin deposition as well as a deacetylase-dependent role to maintain triglyceride homeostasis.