Diabetic cardiomyopathy (DCM) is characterized by metabolic dysregulation and progressive cardiac dysfunction, but the underlying molecular mechanisms remain incompletely understood. Emerging evidence suggests that 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) may play an important role in DCM pathogenesis. This study reveals a novel regulatory mechanism involving SIRT5-mediated post-translational modification of HMGCS2 in DCM pathogenesis using high glucose-treated cardiomyocyte models and DCM mouse models. In DCM models, HMGCS2 was significantly upregulated and found to promote cardiomyocyte pyroptosis, cardiac dysfunction, and myocardial tissue damage. In contrast, SIRT5 exhibited cardioprotective effects under the same conditions. Moreover, SIRT5 overexpression reduced HMGCS2 succinylation while enhancing its ubiquitination and degradation in cardiomyocytes under high glucose conditions. Mechanistically, SIRT5 facilitated ubiquitin-mediated degradation of HMGCS2 at K118 by upregulating the E3 ubiquitin ligase PIAS4. In conclusion, SIRT5 mediated HMGCS2 desuccinylation while promoting PIAS4-dependent HMGCS2 ubiquitination and degradation. This study identified the SIRT5/PIAS4/HMGCS2 axis as a critical regulatory pathway in DCM, suggesting that targeting SIRT5 to influence HMGCS2 post-translational modifications might offer a novel therapeutic approach for DCM.
{"title":"SIRT5 Inhibits HMGCS2 Succinylation and Promotes Its PIAS4-Dependent Ubiquitination to Attenuate Diabetic Cardiomyopathy","authors":"Chahua Huang, Wenqi Xiong, Yingying Xu","doi":"10.1096/fj.202502832R","DOIUrl":"10.1096/fj.202502832R","url":null,"abstract":"<div>\u0000 \u0000 <p>Diabetic cardiomyopathy (DCM) is characterized by metabolic dysregulation and progressive cardiac dysfunction, but the underlying molecular mechanisms remain incompletely understood. Emerging evidence suggests that 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) may play an important role in DCM pathogenesis. This study reveals a novel regulatory mechanism involving SIRT5-mediated post-translational modification of HMGCS2 in DCM pathogenesis using high glucose-treated cardiomyocyte models and DCM mouse models. In DCM models, HMGCS2 was significantly upregulated and found to promote cardiomyocyte pyroptosis, cardiac dysfunction, and myocardial tissue damage. In contrast, SIRT5 exhibited cardioprotective effects under the same conditions. Moreover, SIRT5 overexpression reduced HMGCS2 succinylation while enhancing its ubiquitination and degradation in cardiomyocytes under high glucose conditions. Mechanistically, SIRT5 facilitated ubiquitin-mediated degradation of HMGCS2 at K118 by upregulating the E3 ubiquitin ligase PIAS4. In conclusion, SIRT5 mediated HMGCS2 desuccinylation while promoting PIAS4-dependent HMGCS2 ubiquitination and degradation. This study identified the SIRT5/PIAS4/HMGCS2 axis as a critical regulatory pathway in DCM, suggesting that targeting SIRT5 to influence HMGCS2 post-translational modifications might offer a novel therapeutic approach for DCM.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146108299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leticia Queiroz da Silva, Alexander Leonardo Silva-Junior, Licia C. Silva-Costa, Ivanio Teixeira Borba-Junior, Bradley J. Smith, Edilson Tadeu Andrade, Bruno Kosa Lino Duarte, Marcos Paulo Colella, Thiago Martins Santos, Daniel Martins-de-Souza, Erich Vinicius De Paula
Transient severe neutropenia and thrombocytopenia are frequent during treatment of hematological malignancies and contribute to early mortality through sepsis and bleeding. While neutrophils and platelets are essential for host defense and tissue repair, little is known about immune adaptations during their depletion. In this pilot, discovery phase study, we evaluated the plasma proteome of 10 patients with chemotherapy-induced severe neutropenia and thrombocytopenia, prior to any clinical complication. At sampling, mean neutrophil and platelet counts were 0.15 ± 0.18 × 109/L and 34.6 ± 17.4 × 109/L, respectively. A total of 762 proteins were identified, of which 71 were downregulated and 21 were upregulated in patients compared with healthy controls. Over-representation analyses revealed that most downregulated proteins were related to immune responses, hemostasis, and protein metabolism. Notably, six upregulated proteins (USP8, IGFBP2, RCN1, B2M, LRG1, and C9) also mapped to these pathways, supporting the hypothesis that they may contribute to early systemic responses to chemotherapy-induced myelotoxicity and tissue damage. This exploratory study leveraged a unique clinical window to examine how the human immune system responds to the marked reduction of neutrophils and platelets in the context of tissue and barrier disruption. The downregulation profile suggests impairment of the host's immunothrombotic defense, whereas the upregulated proteins may represent early compensatory mechanisms aimed at preserving homeostasis. Together, these findings provide insights into systemic responses during profound cytopenias and highlight candidate proteins that may mediate early adaptations to hematopoietic and tissue injury in patients undergoing intensive chemotherapy.
{"title":"Plasma Proteomic Profile of Chemotherapy-Induced Severe Neutropenia: A Pilot Discovery Phase Study","authors":"Leticia Queiroz da Silva, Alexander Leonardo Silva-Junior, Licia C. Silva-Costa, Ivanio Teixeira Borba-Junior, Bradley J. Smith, Edilson Tadeu Andrade, Bruno Kosa Lino Duarte, Marcos Paulo Colella, Thiago Martins Santos, Daniel Martins-de-Souza, Erich Vinicius De Paula","doi":"10.1096/fj.202503947RR","DOIUrl":"10.1096/fj.202503947RR","url":null,"abstract":"<p>Transient severe neutropenia and thrombocytopenia are frequent during treatment of hematological malignancies and contribute to early mortality through sepsis and bleeding. While neutrophils and platelets are essential for host defense and tissue repair, little is known about immune adaptations during their depletion. In this pilot, discovery phase study, we evaluated the plasma proteome of 10 patients with chemotherapy-induced severe neutropenia and thrombocytopenia, prior to any clinical complication. At sampling, mean neutrophil and platelet counts were 0.15 ± 0.18 × 10<sup>9</sup>/L and 34.6 ± 17.4 × 10<sup>9</sup>/L, respectively. A total of 762 proteins were identified, of which 71 were downregulated and 21 were upregulated in patients compared with healthy controls. Over-representation analyses revealed that most downregulated proteins were related to immune responses, hemostasis, and protein metabolism. Notably, six upregulated proteins (USP8, IGFBP2, RCN1, B2M, LRG1, and C9) also mapped to these pathways, supporting the hypothesis that they may contribute to early systemic responses to chemotherapy-induced myelotoxicity and tissue damage. This exploratory study leveraged a unique clinical window to examine how the human immune system responds to the marked reduction of neutrophils and platelets in the context of tissue and barrier disruption. The downregulation profile suggests impairment of the host's immunothrombotic defense, whereas the upregulated proteins may represent early compensatory mechanisms aimed at preserving homeostasis. Together, these findings provide insights into systemic responses during profound cytopenias and highlight candidate proteins that may mediate early adaptations to hematopoietic and tissue injury in patients undergoing intensive chemotherapy.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12862286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA editing is a post-transcriptional modification in metazoans and plays a crucial role in environmental adaptation. To elucidate the species specificity of RNA editing in marine mollusks and advance the comprehension of their post-transcriptional modifications, we selected three Tegulidae gastropods, Rochia conus, R. maxima, and Tectus pyramis, from coral reefs in the South China Sea and performed transcriptome-wide RNA editing analysis. The results showed that adenosine-to-inosine (A-to-I) RNA editing was the most prevalent editing type among these three Tegulidae species. The number of A-to-I editing sites (per Gb) and the editing level of these sites varied significantly among species (p < 0.05). Notably, the A-to-I editing density (number of A-to-I edited sites per Gb) of R. conus clustered with that of R. maxima, consistent with their clustering in the adenosine deaminases acting on RNA (ADAR) phylogeny. Furthermore, Gene Ontology analysis revealed that the edited coding genes of R. conus, R. maxima, and T. pyramis were mainly enriched in “neuron projection membrane,” “cellular response to toxic substance,” and “threonine catabolic process,” respectively. These results suggest that the RNA editing patterns of the family Tegulidae are species-specific and that A-to-I RNA editing density is correlated with the ADAR phylogenetic history.
RNA编辑是后生动物的转录后修饰，在环境适应中起着至关重要的作用。为了阐明海洋软体动物RNA编辑的物种特异性，进一步了解其转录后修饰，我们从南海珊瑚礁中选择了三种Tegulidae腹足动物Rochia conus， R. maxima和Tectus pyramis，并进行了转录组范围内的RNA编辑分析。结果表明，腺苷-肌苷（A-to-I） RNA编辑是这3种Tegulidae物种中最普遍的编辑类型。A-to-I编辑位点数量（每Gb）和这些位点的编辑水平在不同物种间差异显著(p
{"title":"Species-Specific Variations of A-to-I RNA Editing in Three Tegulidae Gastropods","authors":"Ya-Jie Zhu, Peng-Jin Zhu, Ming-Ling Liao, Lin-Xuan Ma, Xin-Lei Zhang, Yun-Wei Dong","doi":"10.1096/fj.202503878R","DOIUrl":"10.1096/fj.202503878R","url":null,"abstract":"<div>\u0000 \u0000 <p>RNA editing is a post-transcriptional modification in metazoans and plays a crucial role in environmental adaptation. To elucidate the species specificity of RNA editing in marine mollusks and advance the comprehension of their post-transcriptional modifications, we selected three Tegulidae gastropods, <i>Rochia conus</i>, <i>R. maxima</i>, and <i>Tectus pyramis</i>, from coral reefs in the South China Sea and performed transcriptome-wide RNA editing analysis. The results showed that adenosine-to-inosine (A-to-I) RNA editing was the most prevalent editing type among these three Tegulidae species. The number of A-to-I editing sites (per Gb) and the editing level of these sites varied significantly among species (<i>p</i> < 0.05). Notably, the A-to-I editing density (number of A-to-I edited sites per Gb) of <i>R. conus</i> clustered with that of <i>R. maxima</i>, consistent with their clustering in the adenosine deaminases acting on RNA (ADAR) phylogeny. Furthermore, Gene Ontology analysis revealed that the edited coding genes of <i>R. conus</i>, <i>R. maxima</i>, and <i>T. pyramis</i> were mainly enriched in “neuron projection membrane,” “cellular response to toxic substance,” and “threonine catabolic process,” respectively. These results suggest that the RNA editing patterns of the family Tegulidae are species-specific and that A-to-I RNA editing density is correlated with the ADAR phylogenetic history.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146087857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To better understand the crosstalk between the placenta and the fetus, we aimed to identify proteins released by the placenta into the fetal circulation, as well as proteins taken up by the placenta. This study included 75 healthy term pregnancies, analyzing proteins from plasma samples collected from the umbilical artery and vein using the Somalogic 5000-plex platform. Placental protein release and uptake were determined by comparing protein abundances in the umbilical artery and vein. Additionally, transcriptomic data mapping and gene ontology enrichment analysis were conducted to assign cellular and tissue origin and functions to the proteins. After controlling for the false discovery rate, we identified 766 proteins released by the placenta into the fetal circulation and 926 proteins taken up by the placenta (q < 0.05). Among the released proteins, 70% were previously recognized as expressed in the placenta, affirming their placental origin. Conversely, the proteins taken up from the fetal circulation showed an overrepresentation of proteins specific to bone marrow, tongue, and skeletal muscle, while proteins specific to salivary glands, liver, and placenta were underrepresented. Enrichment analysis revealed molecular functions and biological processes that promote tissue growth and differentiation. Our findings demonstrate a considerable interaction between the placenta and fetus in healthy term pregnancies, with a high number of proteins being exchanged. This research enhances our understanding of the fetal-placental interactions, paving the way for new insights into pathophysiological processes and potential therapeutic strategies in utero.
{"title":"Placental Protein Release and Uptake From the Fetal Circulation in Healthy Term Pregnancies—A Human In Vivo Exploratory Study","authors":"Hilde Bastøe Sellevoll, Ina Jungersen Andresen, Ane Cecilie Westerberg, Maren-Helene Langeland Degnes, Thor Ueland, Manuela Zucknick, Trond Melbye Michelsen","doi":"10.1096/fj.202503626R","DOIUrl":"10.1096/fj.202503626R","url":null,"abstract":"<p>To better understand the crosstalk between the placenta and the fetus, we aimed to identify proteins released by the placenta into the fetal circulation, as well as proteins taken up by the placenta. This study included 75 healthy term pregnancies, analyzing proteins from plasma samples collected from the umbilical artery and vein using the Somalogic 5000-plex platform. Placental protein release and uptake were determined by comparing protein abundances in the umbilical artery and vein. Additionally, transcriptomic data mapping and gene ontology enrichment analysis were conducted to assign cellular and tissue origin and functions to the proteins. After controlling for the false discovery rate, we identified 766 proteins released by the placenta into the fetal circulation and 926 proteins taken up by the placenta (<i>q</i> < 0.05). Among the released proteins, 70% were previously recognized as expressed in the placenta, affirming their placental origin. Conversely, the proteins taken up from the fetal circulation showed an overrepresentation of proteins specific to bone marrow, tongue, and skeletal muscle, while proteins specific to salivary glands, liver, and placenta were underrepresented. Enrichment analysis revealed molecular functions and biological processes that promote tissue growth and differentiation. Our findings demonstrate a considerable interaction between the placenta and fetus in healthy term pregnancies, with a high number of proteins being exchanged. This research enhances our understanding of the fetal-placental interactions, paving the way for new insights into pathophysiological processes and potential therapeutic strategies in utero.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12857601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146087843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N-terminal acetyltransferases are emerging as potential therapeutic targets in cancer. N-alpha-acetyltransferase 30 (NAA30), which serves as the catalytic subunit of the NATC complex. However, the role of NAA30 in ovarian cancer remains unknown. In this study, we found that NAA30 expression was abnormally upregulated in ovarian cancer tissues compared to normal tissues. Functionally, NAA30 promoted cell proliferation, migration, and invasion in ovarian cancer cells. Moreover, in vivo experiments revealed that NAA30 enhanced tumor growth and intraperitoneal metastasis in mouse models. We further explored the regulatory mechanisms underlying NAA30 upregulation. Dual-luciferase assays demonstrated that the transcription factor nuclear receptor subfamily 2 group C member 2 (NR2C2) significantly enhanced the transcriptional activity of the NAA30 promoter. Besides, NR2C2 increased the migratory, invasive, and proliferative capabilities of ovarian cancer cells. Importantly, NAA30 knockdown reversed the pro-tumorigenic effects of NR2C2 overexpression on the malignant phenotype. To identify the downstream targets of NAA30, we employed IP-LC/MS and N-terminal acetylation modification omics. Actin-Related Protein 2/3 Complex Subunit 1B (ARPC1B) was identified as a direct target of NAA30. It was demonstrated that NAA30 protein binds to ARPC1B protein and that NAA30 knockdown enhanced the polyubiquitination of ARPC1B and promotes its degradation. Crucially, the re-expression of ARPC1B in NAA30-silenced cells effectively restored these malignant phenotypes. These findings highlight the critical role of the NR2C2-NAA30-ARPC1B axis in ovarian cancer progression and provide more foundation for the development of more effective treatment strategies for patients with ovarian cancer.
{"title":"N-Alpha-Acetyltransferase 30, Transcriptionally Regulated by NR2C2, Promotes Ovarian Cancer Progression by Mediating ARPC1B Acetylation","authors":"Liwen Xu, Fei Zheng, Dandan Wang, Qing Yang","doi":"10.1096/fj.202502867RR","DOIUrl":"10.1096/fj.202502867RR","url":null,"abstract":"<div>\u0000 \u0000 <p>N-terminal acetyltransferases are emerging as potential therapeutic targets in cancer. N-alpha-acetyltransferase 30 (NAA30), which serves as the catalytic subunit of the NATC complex. However, the role of NAA30 in ovarian cancer remains unknown. In this study, we found that NAA30 expression was abnormally upregulated in ovarian cancer tissues compared to normal tissues. Functionally, NAA30 promoted cell proliferation, migration, and invasion in ovarian cancer cells. Moreover, in vivo experiments revealed that NAA30 enhanced tumor growth and intraperitoneal metastasis in mouse models. We further explored the regulatory mechanisms underlying NAA30 upregulation. Dual-luciferase assays demonstrated that the transcription factor nuclear receptor subfamily 2 group C member 2 (NR2C2) significantly enhanced the transcriptional activity of the NAA30 promoter. Besides, NR2C2 increased the migratory, invasive, and proliferative capabilities of ovarian cancer cells. Importantly, NAA30 knockdown reversed the pro-tumorigenic effects of NR2C2 overexpression on the malignant phenotype. To identify the downstream targets of NAA30, we employed IP-LC/MS and N-terminal acetylation modification omics. Actin-Related Protein 2/3 Complex Subunit 1B (ARPC1B) was identified as a direct target of NAA30. It was demonstrated that NAA30 protein binds to ARPC1B protein and that NAA30 knockdown enhanced the polyubiquitination of ARPC1B and promotes its degradation. Crucially, the re-expression of ARPC1B in NAA30-silenced cells effectively restored these malignant phenotypes. These findings highlight the critical role of the NR2C2-NAA30-ARPC1B axis in ovarian cancer progression and provide more foundation for the development of more effective treatment strategies for patients with ovarian cancer.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146087795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chongxiang Xiong, Ruiyi Gan, Shangrui Li, Baoting Su, Li Zhang, Xinyi Huang, Qiaowen Wang, Ruxin Yi, Shougang Zhuang
5-methylcytosine (m5C) is an abundant RNA modification that participates in various biological processes. This study aims to elucidate the molecular mechanisms by which the m5C methyltransferase NSUN2 regulates renal fibrotic progression. Sirius red staining was employed to evaluate collagen deposition. The m5C methylation levels of BRD4 mRNA were analyzed by MeRIP. The interaction between NSUN2/ALYREF and BRD4 mRNA was validated by RIP and dual-luciferase assay. ChIP was performed to assess H3K27ac enrichment at the PDPK1 promoter region. The expression of fibrosis/epithelial-mesenchymal transition (EMT)-related markers was checked by RT-qPCR, western blotting, or immunohistochemistry. NSUN2 was upregulated in fibrotic renal tissues and cells, accompanied by increased expression of fibrotic and EMT-related proteins. Functionally, NSUN2 promoted TGF-β1-induced EMT in HK-2 cells, and its knockdown alleviated renal fibrosis in UUO rats. Mechanistically, NSUN2 enhanced BRD4 mRNA stability and expression through an m5C-ALYREF-dependent manner. Furthermore, BRD4 increased H3K27ac enrichment in the PDPK1 promoter region, thereby increasing PDPK1 expression, which facilitated the phosphorylation of AKT1 and GSK-3β (ser9) and ultimately induced EMT. NSUN2 stabilizes BRD4 mRNA in an m5C-ALYREF-dependent manner, and upregulated BRD4 enhances PDPK1 expression through H3K27ac modification, thereby modulating the AKT1/GSK-3β pathway and inducing EMT, ultimately promoting renal fibrosis.
{"title":"NSUN2 Exacerbates Renal Fibrosis by Inducing Epithelial-Mesenchymal Transition Through Mediating m5C Modification of BRD4","authors":"Chongxiang Xiong, Ruiyi Gan, Shangrui Li, Baoting Su, Li Zhang, Xinyi Huang, Qiaowen Wang, Ruxin Yi, Shougang Zhuang","doi":"10.1096/fj.202503517R","DOIUrl":"10.1096/fj.202503517R","url":null,"abstract":"<div>\u0000 \u0000 <p>5-methylcytosine (m5C) is an abundant RNA modification that participates in various biological processes. This study aims to elucidate the molecular mechanisms by which the m5C methyltransferase NSUN2 regulates renal fibrotic progression. Sirius red staining was employed to evaluate collagen deposition. The m5C methylation levels of BRD4 mRNA were analyzed by MeRIP. The interaction between NSUN2/ALYREF and BRD4 mRNA was validated by RIP and dual-luciferase assay. ChIP was performed to assess H3K27ac enrichment at the PDPK1 promoter region. The expression of fibrosis/epithelial-mesenchymal transition (EMT)-related markers was checked by RT-qPCR, western blotting, or immunohistochemistry. NSUN2 was upregulated in fibrotic renal tissues and cells, accompanied by increased expression of fibrotic and EMT-related proteins. Functionally, NSUN2 promoted TGF-β1-induced EMT in HK-2 cells, and its knockdown alleviated renal fibrosis in UUO rats. Mechanistically, NSUN2 enhanced BRD4 mRNA stability and expression through an m5C-ALYREF-dependent manner. Furthermore, BRD4 increased H3K27ac enrichment in the PDPK1 promoter region, thereby increasing PDPK1 expression, which facilitated the phosphorylation of AKT1 and GSK-3β (ser9) and ultimately induced EMT. NSUN2 stabilizes BRD4 mRNA in an m5C-ALYREF-dependent manner, and upregulated BRD4 enhances PDPK1 expression through H3K27ac modification, thereby modulating the AKT1/GSK-3β pathway and inducing EMT, ultimately promoting renal fibrosis.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146087870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cardiac hypertrophy represents a complex remodeling process involving extensive reprogramming of gene expression. While transcriptional regulation has been well characterized, post-transcriptional RNA processing has recently emerged as a crucial determinant of cardiac homeostasis. This review summarizes current knowledge of RNA modifications, alternative splicing, mRNA stability, and RNA editing in physiological and pathological hypertrophy. We highlight key epitranscriptomic marks such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), and 7-methylguanosine (m7G), as well as the functions of RNA-binding proteins and adenosine deaminases acting on RNA (ADAR1/2). In exercise-induced hypertrophy, RNA processing contributes to adaptive remodeling by supporting sarcomere organization, calcium handling, and survival pathways, exemplified by RBFOX2-dependent splicing of CACNA1C, RBM20-directed regulation of titin isoforms, and METTL14-mediated m6A signaling that enhances Akt activity. Conversely, pathological stress leads to dysregulated RNA programs that promote maladaptive remodeling through aberrant splice variants, perturbation of circular RNAs, and persistent pro-inflammatory signaling, thereby facilitating contractile dysfunction and progression to heart failure. Context-dependent regulators, including METTL3, YTHDF2, RBM24, and ADAR2, orchestrate the balance between adaptive and maladaptive responses. Targeting specific nodes, such as METTL3-driven m6A methylation or RBM24-dependent splicing fidelity, may provide innovative therapeutic strategies. Advances in RNA-targeted interventions, including ADAR-mediated editing and small molecule inhibitors of methyltransferases, highlight the translational potential of RNA processing as a novel avenue for precision cardiovascular therapy.
{"title":"RNA Processing in Cardiac Hypertrophy: Coordinating Physiological Adaptation and Pathological Remodeling","authors":"Mengling Peng, Yu Fu, Cong Qin, Jingpeng Jin, Shanshan Zhou","doi":"10.1096/fj.202503525R","DOIUrl":"10.1096/fj.202503525R","url":null,"abstract":"<p>Cardiac hypertrophy represents a complex remodeling process involving extensive reprogramming of gene expression. While transcriptional regulation has been well characterized, post-transcriptional RNA processing has recently emerged as a crucial determinant of cardiac homeostasis. This review summarizes current knowledge of RNA modifications, alternative splicing, mRNA stability, and RNA editing in physiological and pathological hypertrophy. We highlight key epitranscriptomic marks such as N6-methyladenosine (m<sup>6</sup>A), 5-methylcytosine (m<sup>5</sup>C), and 7-methylguanosine (m<sup>7</sup>G), as well as the functions of RNA-binding proteins and adenosine deaminases acting on RNA (ADAR1/2). In exercise-induced hypertrophy, RNA processing contributes to adaptive remodeling by supporting sarcomere organization, calcium handling, and survival pathways, exemplified by RBFOX2-dependent splicing of CACNA1C, RBM20-directed regulation of titin isoforms, and METTL14-mediated m<sup>6</sup>A signaling that enhances Akt activity. Conversely, pathological stress leads to dysregulated RNA programs that promote maladaptive remodeling through aberrant splice variants, perturbation of circular RNAs, and persistent pro-inflammatory signaling, thereby facilitating contractile dysfunction and progression to heart failure. Context-dependent regulators, including METTL3, YTHDF2, RBM24, and ADAR2, orchestrate the balance between adaptive and maladaptive responses. Targeting specific nodes, such as METTL3-driven m<sup>6</sup>A methylation or RBM24-dependent splicing fidelity, may provide innovative therapeutic strategies. Advances in RNA-targeted interventions, including ADAR-mediated editing and small molecule inhibitors of methyltransferases, highlight the translational potential of RNA processing as a novel avenue for precision cardiovascular therapy.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202503525R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146087883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
There is ample evidence that exercise contributes to prevention and treatment of myocardial infarction. Although transmembrane protein fibronectin type III domain protein 5 (FNDC5)/Irisin is known to mediate the protective effects of exercise on ischemic heart, its effects and mechanisms on mitochondria after myocardial infarction are not fully defined. We randomized wild and FNDC5 knockout (KO) mice on which to construct a post-infarction exercise rehabilitation model, and subsequently compared the differences in cardiac and myocardial mitochondrial structure and function between groups; the FNDC5/Irisin-AMPK-Sirt1 mitochondrial pathway was further assessed by applying recombinant human Irisin, FNDC5 and/or Sirt1 knockdown (KD) treatment to neonatal mouse cardiomyocytes. Transmission electron microscopy was used to examine mitochondrial structure, Oxygraph-2k was used to measure mitochondrial function, and immunoblotting was used to assess mitochondrial genesis, mitophagy marker proteins, and pathway-related proteins. FNDC5KO induced abnormalities of myocardial mitochondrial genesis and mitophagy, weakened the improvement effect of exercise toward mitochondrial injury and was associated with deteriorated cardiac function after myocardial infarction. Sirt1KD weakened the FNDC5/Irisin-mediated regulatory effect of exercise on mitochondrial genesis and mitophagy in primary cardiomyocytes. Exercise induced FNDC5/Irisin is an important regulator of the ameliorative effects of Sirt1 on cardiac function and mitochondrial remodeling during infarction rehabilitation.
{"title":"Deficiency of FNDC5/Irisin Impairs the Protective Effect of Exercise Against Post-Infarction Myocardial Mitochondrial Injury","authors":"Shuguang Qin, Yixuan Ma, Wujing Ren, Yue Xi, Hangzhuo Li, Wenyan Bo, Zhenjun Tian","doi":"10.1096/fj.202500863RRRR","DOIUrl":"10.1096/fj.202500863RRRR","url":null,"abstract":"<div>\u0000 \u0000 <p>There is ample evidence that exercise contributes to prevention and treatment of myocardial infarction. Although transmembrane protein fibronectin type III domain protein 5 (FNDC5)/Irisin is known to mediate the protective effects of exercise on ischemic heart, its effects and mechanisms on mitochondria after myocardial infarction are not fully defined. We randomized wild and <i>FNDC5</i> knockout (KO) mice on which to construct a post-infarction exercise rehabilitation model, and subsequently compared the differences in cardiac and myocardial mitochondrial structure and function between groups; the FNDC5/Irisin-AMPK-Sirt1 mitochondrial pathway was further assessed by applying recombinant human Irisin, <i>FNDC5</i> and/or <i>Sirt1</i> knockdown (KD) treatment to neonatal mouse cardiomyocytes. Transmission electron microscopy was used to examine mitochondrial structure, Oxygraph-2k was used to measure mitochondrial function, and immunoblotting was used to assess mitochondrial genesis, mitophagy marker proteins, and pathway-related proteins. <i>FNDC5</i><sup>KO</sup> induced abnormalities of myocardial mitochondrial genesis and mitophagy, weakened the improvement effect of exercise toward mitochondrial injury and was associated with deteriorated cardiac function after myocardial infarction. <i>Sirt1</i><sup>KD</sup> weakened the FNDC5/Irisin-mediated regulatory effect of exercise on mitochondrial genesis and mitophagy in primary cardiomyocytes. Exercise induced FNDC5/Irisin is an important regulator of the ameliorative effects of Sirt1 on cardiac function and mitochondrial remodeling during infarction rehabilitation.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146087837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shaobo Wang, Xue Cai, Chanyan Weng, Miaozhu Su, Qunfeng Yang, Bo Chen, Jincheng Zeng
The extremely complex, multivariate, and systemic pathophysiology of diabetic nephropathy is brought on by prolonged exposure to hyperglycemia, making the quest for the best therapeutic approach crucial and urgent. Accumulating evidence suggests that pyroptosis and inflammation contribute to the development of diabetic nephropathy. Zinc fingers and homeoboxes 2 (ZHX2) were recently discovered to be a new regulator of inflammatory response. However, the role and potential molecular mechanisms of ZHX2 in diabetic nephropathy remain unclear. Exosomes derived from gingival mesenchymal stem cells (GMSCs-Exo) were successfully isolated and characterized. GMSCs-Exo reversed high glucose-induced podocyte pyroptosis and inflammation. ZHX2 was highly expressed in GMSCs-Exo. Furthermore, ZHX2 derived from GMSCs-Exo reversed podocyte pyroptosis and inflammation induced by HG. Additionally, ZHX2 was enriched in the FABP4 promoter region and transcriptionally inhibited the mRNA and protein levels of FABP4. GMSCs-Exo-derived ZHX2 abolished HG-induced podocyte pyroptosis and inflammation by inhibiting FABP4 and blocking the advanced glycation endproducts/the receptor of advanced glycation endproducts/NOD-like receptor family pyrin domain-containing 3 (AGEs/RAGE/NLRP3) pathway. Similarly, GMSCs-Exo-derived ZHX2 alleviated renal injury, pyroptosis, and inflammation in diabetic nephropathy mice. In conclusion, our findings demonstrated that ZHX2 protects against diabetic nephropathy by binding to the FABP4 promoter and reducing the expression of FABP4. We also showed that GMSCs-Exo-derived ZHX2 reversed HG-induced podocyte pyroptosis and inflammation by inhibiting the AGEs/RAGE/NLRP3 pathway. ZHX2 derived from GMSCs-Exo also alleviated tubular injury, pyroptosis, and inflammation in diabetic nephropathy mice. The therapeutic potential of targeting ZHX2 to treat diabetic nephropathy is clarified by these findings.
{"title":"GMSCs-Derived Exosome ZHX2 Improves Diabetes Nephropathy by Blocking AGEs/RAGE/NLRP3 Pathway to Inhibit Podocyte Pyroptosis and Inflammatory Response","authors":"Shaobo Wang, Xue Cai, Chanyan Weng, Miaozhu Su, Qunfeng Yang, Bo Chen, Jincheng Zeng","doi":"10.1096/fj.202503753R","DOIUrl":"10.1096/fj.202503753R","url":null,"abstract":"<div>\u0000 \u0000 <p>The extremely complex, multivariate, and systemic pathophysiology of diabetic nephropathy is brought on by prolonged exposure to hyperglycemia, making the quest for the best therapeutic approach crucial and urgent. Accumulating evidence suggests that pyroptosis and inflammation contribute to the development of diabetic nephropathy. Zinc fingers and homeoboxes 2 (ZHX2) were recently discovered to be a new regulator of inflammatory response. However, the role and potential molecular mechanisms of ZHX2 in diabetic nephropathy remain unclear. Exosomes derived from gingival mesenchymal stem cells (GMSCs-Exo) were successfully isolated and characterized. GMSCs-Exo reversed high glucose-induced podocyte pyroptosis and inflammation. ZHX2 was highly expressed in GMSCs-Exo. Furthermore, ZHX2 derived from GMSCs-Exo reversed podocyte pyroptosis and inflammation induced by HG. Additionally, ZHX2 was enriched in the FABP4 promoter region and transcriptionally inhibited the mRNA and protein levels of FABP4. GMSCs-Exo-derived ZHX2 abolished HG-induced podocyte pyroptosis and inflammation by inhibiting FABP4 and blocking the advanced glycation endproducts/the receptor of advanced glycation endproducts/NOD-like receptor family pyrin domain-containing 3 (AGEs/RAGE/NLRP3) pathway. Similarly, GMSCs-Exo-derived ZHX2 alleviated renal injury, pyroptosis, and inflammation in diabetic nephropathy mice. In conclusion, our findings demonstrated that ZHX2 protects against diabetic nephropathy by binding to the FABP4 promoter and reducing the expression of FABP4. We also showed that GMSCs-Exo-derived ZHX2 reversed HG-induced podocyte pyroptosis and inflammation by inhibiting the AGEs/RAGE/NLRP3 pathway. ZHX2 derived from GMSCs-Exo also alleviated tubular injury, pyroptosis, and inflammation in diabetic nephropathy mice. The therapeutic potential of targeting ZHX2 to treat diabetic nephropathy is clarified by these findings.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146068293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Obesity is one of the most prevalent public health issues worldwide, which substantially increases the risk of many metabolic disorders. Anti-obesity medications and bariatric surgery are clinical treatments for obesity, but suffer from certain limitations. Gene therapy with effective and safe targets provides a novel approach for obesity intervention. Tks4 has been shown to play an essential role in preadipocyte to adipocyte differentiation. However, it is still elusive if it could be a drug target against obesity in vivo. Here, we found the expression levels of Tks4 correlate with adipocyte development and hypertrophy in mice. By generating a Tks4 KO mouse model, we showed Tks4 deletion significantly restricted adipocyte hypertrophy and reduced blood glucose and lipid levels. We further used an adeno-associated viral (AAV) vector to mediate sustained Tks4 silencing. For a single administration, the adipocyte hypertrophy at the injection site was significantly reduced in a dosage-dependent manner. The TAG biosynthesis defect was also verified by lipidomics analysis of the infected WAT, though an elevation of TAG in blood was also detected. These data support the potential of Tks4 gene therapy to treat obesity.
{"title":"Tks4-Targeted Gene Therapy Inhibited White Adipocyte Hypertrophy in Mice","authors":"Meng Tian, Jingwen Deng, Yuzhu Hong, Ruitong Liu, Shengnan Li, Xiaoxiao He","doi":"10.1096/fj.202503709RR","DOIUrl":"10.1096/fj.202503709RR","url":null,"abstract":"<p>Obesity is one of the most prevalent public health issues worldwide, which substantially increases the risk of many metabolic disorders. Anti-obesity medications and bariatric surgery are clinical treatments for obesity, but suffer from certain limitations. Gene therapy with effective and safe targets provides a novel approach for obesity intervention. Tks4 has been shown to play an essential role in preadipocyte to adipocyte differentiation. However, it is still elusive if it could be a drug target against obesity in vivo. Here, we found the expression levels of Tks4 correlate with adipocyte development and hypertrophy in mice. By generating a <i>Tks4</i> KO mouse model, we showed <i>Tks4</i> deletion significantly restricted adipocyte hypertrophy and reduced blood glucose and lipid levels. We further used an adeno-associated viral (AAV) vector to mediate sustained <i>Tks4</i> silencing. For a single administration, the adipocyte hypertrophy at the injection site was significantly reduced in a dosage-dependent manner. The TAG biosynthesis defect was also verified by lipidomics analysis of the infected WAT, though an elevation of TAG in blood was also detected. These data support the potential of <i>Tks4</i> gene therapy to treat obesity.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12850628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146068357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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