m6A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation.

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction (MI) can lead to heart failure. RNA N6-methyladenosine (m6A) methylation has been shown to play a pivotal role in the occurrence and development of many illnesses. In investigating the biological function of the m6A reader YTHDF1 in cardiac fibrosis, adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts, and MI surgery in vivo and transforming growth factor-ß (TGF-ß)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models. Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis, whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development. Mechanistically, zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter. YTHDF1 augmented AXL translation and activated the TGF-ß-Smad2/3 signaling pathway, thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis. Consistently, our data indicated that YTHDF1 was involved in activation, proliferation, and migration to participate in cardiac fibrosis in vitro. Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

Innovative pharmacotherapy for hepatic metabolic and chronic inflammatory diseases in China.

Liver disease constitutes a significant global health concern, particularly in China where it has distinctive characteristics. China grapples with a staggering 300 million cases, predominantly due to hepatitis B and metabolic non-alcoholic fatty liver disease. Additionally, hepatocellular carcinoma has become a prevalent which is a lethal type of cancer. Despite the scarcity of innovative treatment options, Chinese hepatologists and researchers have achieved notable breakthroughs in the prevention, diagnosis, management and treatment of liver diseases. Traditional Chinese medicines have found widespread application in the treatment of various liver ailments owing to their commendable pharmacological efficacy and minimal side effects. Furthermore, there is a growing body of research in extracellular vesicles, cell therapy and gene therapy, offering new hope in the fight against liver diseases. This paper provides a comprehensive overview of the epidemiological characteristics of liver diseases and the diverse array of treatments that Chinese scholars and scientists have pursued in critical field.

YTHDF2 Promotes Cardiac Ferroptosis via Degradation of SLC7A11 in Cardiac Ischemia-Reperfusion Injury.

Aims: Myocardial ischemia-reperfusion (I/R) injury facilitates cardiomyocyte death and endangers human health. N6-methyladenosine (m6A) methylation plays a critical role in cardiovascular diseases. The m6A reader YTHDF2 identifies m6A-modified RNA and promotes target RNA degradation. Hence, we hypothesized that YTHDF2 affects I/R injury by regulating RNA stability. Results: Both messenger RNA (mRNA) and protein levels of YTHDF2 were upregulated in I/R mice and hypoxia-reoxygenation (H/R)-induced cardiomyocytes. Silencing endogenous YTHDF2 abrogated cardiac dysfunction and lowered the infarct size in I/R mice, and the forced expression of YTHDF2 aggravated these adverse pathological processes. Consistently, the protective effect of silencing YTHDF2 occurred in cardiomyocytes exposed to H/R and erastin. Further, RNA-Seq and RNA-binding protein immunoprecipitation (RIP) revealed that YTHDF2 recognized the m6A modification sites of the ferroptosis-related gene solute carrier family 7 member 11 (SLC7A11) mRNA to promote its degradation both in vivo and in vitro. Inhibition of SLC7A11 impaired cardiac function, increased infarct size, and the release of lactate dehydrogenase (LDH) in I/R mice after silencing YTHDF2. The beneficial effects of si-YTHDF2 on H/R injury were reversed by co-transfection with SLC7A11-specific siRNA (si-SLC7A11), which substantially exacerbated ferroptosis and the production of reactive oxygen species. Innovation and Conclusion: The cardioprotective effects of silencing YTHDF2 are accomplished by increasing SLC7A11 stability and expression, reducing ferroptosis, and providing novel potential therapeutic targets for treating ischemic cardiac diseases.

The circular RNA circHelz enhances cardiac fibrosis by facilitating the nuclear translocation of YAP1.

Cardiac fibrosis is a common pathological change in the development of heart disease. Circular RNA (circRNA) has been shown to be related to the occurrence and development of various cardiovascular diseases. This study aimed to evaluate the effects and potential mechanisms of circHelz in cardiac fibrosis. Knockdown of circHelz alleviated cardiac fibrosis and myocardial fibroblast activation induced by myocardial infarction (MI) or angiotensin II (AngII) in vivo and transforming growth factor-ß (TGF-ß) in vitro. Overexpression of circHelz exacerbated cell proliferation and differentiation. Mechanistically, nuclear factor of activated T cells, cytoplasmic 2 (NFATc2) was found to act as a transcriptional activator to upregulate the expression of circHelz. The increased circHelz was demonstrated to bind to Yes-associated protein (YAP) and facilitate its localization in the nucleus to promote cell proliferation and growth. Moreover, silencing YAP1 reversed the detrimental effects caused by circHelz in vitro, as indicated by the observed decreases in cell viability, fibrotic marker expression levels, proliferation and migration. Collectively, the protective effect of circHelz knockdown against cardiac fibrosis injury is accomplished by inhibiting the nuclear translocation of YAP1. Thus, circHelz may be a novel target for the prevention and treatment of cardiovascular disease.