The m6A reader YTHDF3-mediated PRDX3 translation alleviates liver fibrosis

Sun, Ruimin; Tian, Xinyao; Li, Yang; Zhao, Yan; Wang, Zhecheng; Hu, Yan; Zhang, Lijun; Wang, Yue; Gao, Dongyan; Zheng, Shusen; Yao, Jihong

doi:10.1016/j.redox.2022.102378

Cited by 36 publications

(26 citation statements)

References 52 publications

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“…Assembly of a target gene-specific shRNA or target gene and AAV containing a GFAP promoter can lead to knockdown or overexpression of the target gene in HSCs in vivo. [36][37][38] In mouse hepatic fibrosis models, HDD improves hepatic fibrosis and upregulates Smad7 expression in HSCs, whereas AAV9-shSmad7 blocks HDD function. Therefore,…”

Section: Discussionmentioning

confidence: 99%

“…To further confirm that Smad7 is an important antifibrotic molecule for HDD in vivo, we used AAV9‐shSmad7 containing the GFAP promoter to knockdown Smad7 expression in HSCs. Assembly of a target gene‐specific shRNA or target gene and AAV containing a GFAP promoter can lead to knockdown or overexpression of the target gene in HSCs in vivo 36–38 . In mouse hepatic fibrosis models, HDD improves hepatic fibrosis and upregulates Smad7 expression in HSCs, whereas AAV9‐shSmad7 blocks HDD function.…”

Section: Discussionmentioning

confidence: 99%

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Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7‐mediated degradation of TGFβRI

Xu,

Guo,

Luo

et al. 2023

Liver International

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Background and PurposeLiver fibrosis is a wound‐healing reaction that eventually leads to cirrhosis. Hydronidone is a new pyridine derivative with the potential to treat liver fibrosis. In this study, we explored the antifibrotic effects of hydronidone and its potential mode of action.MethodsThe anti‐hepatic fibrosis effects of hydronidone were studied in carbon tetrachloride (CCl4)‐ and 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC)‐ induced animal liver fibrosis. The antifibrotic mechanisms of hydronidone were investigated in hepatic stellate cells (HSCs). The antifibrotic effect of hydronidone was further tested after Smad7 knockdown in HSCs in mouse models of fibrosis.ResultsIn animal models, hydronidone attenuated liver damage and collagen accumulation, and reduced the expression of fibrosis‐related genes. Hydronidone decreased the expression of fibrotic genes in HSCs. Impressively, hydronidone significantly upregulated Smad7 expression and promoted the degradation of transforming growth factor β receptor I (TGFβRI) in HSCs and thus inhibited the TGFβ‐Smad signalling pathway. Specific knockdown of Smad7 in HSCs in vivo blocked the antifibrotic effect of hydronidone.ConclusionHydronidone ameliorates liver fibrosis by inhibiting HSCs activation via Smad7‐mediated TGFβRI degradation. Hydronidone is a potential drug candidate for the treatment of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7‐mediated degradation of TGFβRI

Xu,

Guo,

Luo

et al. 2023

Liver International

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“…Oxidative stress occurs at the beginning and accompanies the whole process of TBI and is one of the significant mechanisms. A large number of studies have confirmed that m 6 A plays an important role in oxidative stress [ 151 , 185 , 186 , 187 , 188 ]. Anders et al first found that the m 6 A signal accumulates in reaction to oxidative stress in stress granules and that YTHDF3 promotes target mRNA translocation into stress granules [ 189 ].…”

Section: The Role Of M 6 a Rna Modification In Tbi...mentioning

confidence: 99%

The Potential Role of m6A in the Regulation of TBI-Induced BGA Dysfunction

et al. 2022

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The brain–gut axis (BGA) is an important bidirectional communication pathway for the development, progress and interaction of many diseases between the brain and gut, but the mechanisms remain unclear, especially the post-transcriptional regulation of BGA after traumatic brain injury (TBI). RNA methylation is one of the most important modifications in post-transcriptional regulation. N6-methyladenosine (m6A), as the most abundant post-transcriptional modification of mRNA in eukaryotes, has recently been identified and characterized in both the brain and gut. The purpose of this review is to describe the pathophysiological changes in BGA after TBI, and then investigate the post-transcriptional bidirectional regulation mechanisms of TBI-induced BGA dysfunction. Here, we mainly focus on the characteristics of m6A RNA methylation in the post-TBI BGA, highlight the possible regulatory mechanisms of m6A modification in TBI-induced BGA dysfunction, and finally discuss the outcome of considering m6A as a therapeutic target to improve the recovery of the brain and gut dysfunction caused by TBI.

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“…Ceramide is a key tuner of YAP/TAZ pathway and stimulation of HSCs, as well as gives prominence to aCDase as a potential mark for LF therapy [152] . PRDX3 is also a key regulator of LF, and targeting the YTHDF3/PRDX3 axis in HSC may be a promising treatment for LF [153] . The accumulation of succinate in fatty liver cells may activate HSCs via the GPR-91 receptor signaling pathway, and the liable molecular mechanism of action is that hepatocytes and HSCs are crosstalked via the GPR-91 signaling pathway [154] .…”

Section: Other Pathwaysmentioning

confidence: 99%

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Zheng

Yang

Luo

et al. 2022

Preprint

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Liver fibrosis (LF) is a trauma repair process carried out by the liver in response to various acute and chronic liver injuries, featured by excessive proliferation as well as abnormal dismissal of extracellular matrix as the main pathological features, and its continuous development will deteriorate into cirrhosis, liver cancer as well as other illnesses. The occurrence of LF is closely related to Hepatic stellate cells (HSCs) stimulation, and intervention in HSCs proliferation is expected to reverse LF. Plant-based small molecule drugs have anti-LF effects, and their mechanisms of action are related to anti-inflammation, anti-oxidative stress, as well as inhibition of abnormal accumulation of extracellular matrix. Consequently, new agents for HSCs will be required to furnish a possible curative response. Small-molecule natural products might be attractive for LF therapy. That is because they not only have the effect against HSCs, but also have excellent qualities such as low toxic side effects and easy availability from the perspective of safety and cost. In this review, we provide an updated review of the signal transduction pathways involved in HSCs and small-molecule natural products targeting HSCs reported in the past 3 years at home and abroad, with the aim of providing new ideas for the development of plant-based small molecule drugs targeting HSCs to reverse LF.

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The m6A reader YTHDF3-mediated PRDX3 translation alleviates liver fibrosis

Cited by 36 publications

References 52 publications

Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7‐mediated degradation of TGFβRI

Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7‐mediated degradation of TGFβRI

The Potential Role of m6A in the Regulation of TBI-Induced BGA Dysfunction

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

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