Publications

2025

1. Cells

   The cGAS/STING Pathway: Friend or Foe in Regulating Cardiomyopathy

   Weiyue Wang, Yuanxu Gao, Hyun Kyoung Lee, and 4 more authors

   Cells, 2025

   Abs DOI

   Inflammation is a central hallmark of cardiomyopathy, where misdirected immune responses contribute to chronic myocardial dysfunction. Among the emerging molecular mechanisms implicated in this process, the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway has garnered increasing attention. Acting as a key cytosolic DNA sensor, the cGAS/STING pathway orchestrates inflammatory responses triggered by microbial infections or endogenous cellular stressors such as autophagy and apoptosis. Despite its pivotal role, the precise molecular mechanisms regulating this pathway and its role in cardiomyopathy-associated inflammation remain poorly understood and subject to ongoing debate. To address this scientific gap, we first reviewed key findings on cGAS/STING signaling in various forms of cardiomyopathy, drawing from in vivo and in vitro studies, as well as clinical samples. In the next step, we explored how the cGAS/STING pathway could be modulated by specific agonists and antagonists in the context of cardiac disease. Finally, by integrating publicly available human single-cell RNA sequencing (scRNA-seq) data and a systematic literature review, we identified existing molecular interventions and highlighted promising therapeutic targets aimed at mitigating cGAS/STING-driven inflammation. This comprehensive approach emphasizes the therapeutic potential of targeting the cGAS/STING pathway and provides a foundation for developing novel interventions aimed at alleviating inflammatory cardiomyopathy and improving patient outcomes. Future studies will be essential to validate these findings and facilitate their translation into clinical practice.

2. JCI Insight

   

   Cardiac Myocyte Cytosolic Self-DNA Contributes to the Pathogenesis of Desmoplakin-Cardiomyopathy

   Weiyue Wang, Benjamin Cathcart, Quoc D Nguyen, and 6 more authors

   JCI insight, 2025

   Abs DOI

   Hereditary cardiomyopathies are the prototypic forms of heart failure and major causes of sudden cardiac death. The genome in cardiomyopathies is exposed to internal stressors, which damage the DNA and activate the DNA damage response (DDR) pathways. We set to determine whether the DDR pathways were activated and pathogenic in an established mouse model of desmoplakin (DSP)-cardiomyopathy generated upon deletion of the Dsp gene in cardiac myocytes (Myh6-McmTam:DspF/F). The mice exhibited premature death, cardiac dysfunction, myocardial cell death, fibrosis, and increased expression levels of the pro-inflammatory cytokines, consistent with the phenotype of human DSP-cardiomyopathy. Cytosolic nuclear self-DNA (nDNA) and mitochondrial DNA (mtDNA) were increased in cardiac myocyte cytosol in the Myh6-McmTam:DspF/F mice. Likewise, the DDR pathway proteins, including the cyclic GMP-AMP synthase (CGAS), stimulator of interferon response 1 (STING1) were upregulated as were the transcript levels of interferon response factor 3 (IRF3) and the nuclear factor κB (NFκB) target genes. Deletion of the Mb21d1 gene encoding CGAS in the Myh6-McmTam:DspF/F mice prolonged survival, improved cardiac function, attenuated fibrosis, and reduced cell death. Thus, cytosolic nDNA and mtDNA are increased and the DDR pathways are activated and pathogenic in a mouse model of DSP-cardiomyopathy, whereas genetic blockade of CGAS is salubrious.

3. JMCC

   

   Deregulated nutrient response in ttntv cardiomyopathy can be repaired via Erk inhibition for cardioprotective effects

   Feixiang Yan, Weiyue Wang, Maryam Moossavi, and 3 more authors

   Journal of Molecular and Cellular Cardiology, 2025

   Abs DOI

   Background: Truncating TITIN variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM); however, key pathological signaling pathways remain elusive. We recently established a zebrafish model of TTNtv DCM and developed a F0-based genome editing technology for the rapid screening of genetic modifiers. Methods: We screened multiple known cardiomyopathy signaling pathways through a F0-based genetic assay using a zebrafish ttntv DCM model. Because ERK signaling was identified from the screen, which was also independently identified as an altered signaling pathway during a cardiac transcriptomic study of the ttntv DCM model, we then assessed modifying effects of differentially expressed genes (DEGs) in ERK signaling. Results: erk1 and mek1 have been identified as therapeutic modifiers for ttntv DCM. Consistent with their modifying effects, we observed increased levels of phosphorylated Erk1 protein in ttntv adult zebrafish. Mechanistically, we showed that enhanced ERK signaling results in deregulated nutrient response, as indicated by the muted response of phosphorylated ribosomal protein S6 (pS6) expression in the heart during the fasting-refeeding cycle. The inhibition of ERK signaling is sufficient to rescue deregulated nutrient response and mitigate cardiac dysfunction. Further genetic screens of DEGs in ERK signaling identified ppp1r10, encoding a protein phosphatase 1 (PP1) regulatory subunit that regulates Mek1/Erk1 phosphorylation, as another therapeutic modifier gene that also rescues deregulated nutrient response. Conclusions: An Erk - nutrient response signaling axis is disrupted in ttntv cardiomyopathy, which can be repaired by the inhibition of erk1, mek1 or ppp1r10, suggesting a new therapeutic avenue for TTNtv DCM.

4. JMCC PLUS

   Dysregulated nutrient sensing is a pathological event in zebrafish TTNtv cardiomyopathy that can be repaired via inhibiting ERK signaling

   Feixiang Yan, Weiyue Wang, Maryam Moossavi, and 3 more authors

   Journal of Molecular and Cellular Cardiology Plus, 2025

   Abs DOI

   Background: Truncating TITIN variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM). However, pathological pathways in TTNtv DCM remain elusive, and mechanism-based therapies are needed. We recently established a zebrafish model on TTNtv DCM and a F0-based genome editing technology in adult zebrafish for rapidly screening genetic modifiers of an inherited cardiomyopathy. Objectives: To discover new pathological pathways and relevant therapeutic strategies for TTNtv DCM via genetic screens in zebrafish. Methods: We screened several known cardiomyopathy signaling pathways via F0-based genetic screens using a zebrafish ttntv DCM model. We then defined cardiac transcriptomic changes, identified differentially expressed genes (DEGs), and further tested potential modifying effects of DEGs on ttntv DCM. Results: erk1 and mek1, encoding two proteins in the Erk signaling pathway, were identified as therapeutic modifiers for ttntv DCM. Consistent with their modifying effects, we noted increased phosphorylated Erk1 levels in ttntv adult zebrafish. Mechanistically, the increased ERK signaling is associated with dysregulated nutrient sensing as reflected in altered dynamic expression of cardiac pS6 during fasting-refeeding cycle. Inhibition of Erk signaling is sufficient to rescue dysregulated nutrient sensing and to mitigate cardiac dysfunction. Further genetic screens of DEGs in Erk signaling identified ppp1r10 and ppp2ca as two additional therapeutic modifier genes. However, inhibition of ppp1r10, but not ppp2ca, is able to rescue dysregulated nutrient sensing and to repair aberrantly increased ERK signaling. Conclusions: Dysregulated nutrient sensing in ttntv cardiomyopathy can be repaired by inhibition of erk1, mek1 or ppp1r10, which represents a new therapeutic avenue for ttntv DCM.

2022

1. Phenomics

   Large-scale proteomics data reveal integrated prognosis-related protein signatures and role of SMAD4 and RAD50 in prognosis and immune infiltrations of prostate cancer microenvironment

   Aihetaimujiang Anwaier, Shu-Xuan Zhu, Xi Tian, and 8 more authors

   Phenomics, 2022

   Abs DOI

   As prostate cancer (PCa) is one of the most commonly diagnosed cancer worldwide, identifying potential prognostic biomarkers is crucial. In this study, the survival information, gene expression, and protein expression data of 344 PCa cases were collected from the Cancer Proteome Atlas (TCPA) and the Cancer Genome Atlas (TCGA) to investigate the potential prognostic biomarkers. The integrated prognosis-related proteins (IPRPs) model was constructed based on the risk score of each patients using machine-learning algorithm. IPRPs model suggested that Elevated RAD50 expression (p = 0.016) and down-regulated SMAD4 expression (p = 0.017) were significantly correlated with unfavorable outcomes for PCa patients. Immunohistochemical (IHC) staining and western blot (WB) analysis revealed significant differential expression of SMAD4 and RAD50 protein between tumor and normal tissues in validation cohort. According to the overall IHC score, patients with low SMAD4 (p < 0.0001) expression and high RAD50 expression (p = 0.0001) were significantly correlated with poor outcomes. Besides, expression of SMAD4 showed significantly negative correlation with most immune checkpoint molecules, and the low SMAD4 expression group exhibited significantly high levels of LAG3 (p < 0.05), TGFβ (p < 0.001), and PD-L1 (p < 0.05) compared with the high SMAD4 expression group in the validation cohort. Patients with low SMAD4 expression had significantly higher infiltration of memory B cells (p = 0.002), CD8 + T cells (p < 0.001), regulatory T cells (p = 0.006), M2-type macrophages (p < 0.001), and significantly lower infiltration of naïve B cells (p = 0.002), plasma cells (p < 0.001), resting memory CD4 + T cells (p < 0.001) and eosinophils (p = 0.045). Candidate proteins were mainly involved in antigen processing and presentation, stem cell differentiation, and type I interferon pathways.