ALKBH5 ameliorated liver fibrosis and suppressed HSCs activation via triggering PTCH1 activation in an m6A dependent manner

Yang, Jingjing; Wang, Juan; Yang, Yang; Yang, Yan; Li, Jun; Lu, Dong; Lu, Chao

doi:10.1016/j.ejphar.2022.174900

Cited by 27 publications

(17 citation statements)

References 32 publications

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“…Second, deletion of ALKBH5 was reported to be associated with worsening clinical liver fibrosis in collected clinical liver fibrosis samples. It was confirmed that ALKBH5 expression was significantly lower in human liver fibrosis tissues in mRNA, protein, and immunohistochemical staining compared to controls, and that increased expression of COL1A1 and α-SMA was also consistent with the severity of liver fibrosis detected with Sirius red and Masson trichrome staining ( Yang et al, 2022 ). And hepatic myofibroblasts with MeCP2 siRNA knockdown expressed more PTCH1 mRNA and protein ( Yang et al, 2013 ).…”

Section: Liver Fibrosis-related Genes and Dna Methylationmentioning

confidence: 62%

“…Firstly, in vitro activation of HSCs and CCl 4 -induced liver fibrosis models in mice showed that PTCH1 affects HSC activation through the Gli1 and Smad3 signaling pathways. When PTCH1 is hypermethylated, PTCH1 expression is downregulated and HSCs are activated ( Yang et al, 2022 ), while ALKBH5 upregulates PTCH1 expression and improves or alleviates liver fibrosis ( Chen et al, 2012 ). Second, deletion of ALKBH5 was reported to be associated with worsening clinical liver fibrosis in collected clinical liver fibrosis samples.…”

Section: Liver Fibrosis-related Genes and Dna Methylationmentioning

confidence: 99%

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Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis

et al. 2023

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Liver fibrosis is a repair response to injury caused by various chronic stimuli that continually act on the liver. Among them, the activation of hepatic stellate cells (HSCs) and their transformation into a myofibroblast phenotype is a key event leading to liver fibrosis, however the mechanism has not yet been elucidated. The molecular basis of HSC activation involves changes in the regulation of gene expression without changes in the genome sequence, namely, via epigenetic regulation. DNA methylation is a key focus of epigenetic research, as it affects the expression of fibrosis-related, metabolism-related, and tumor suppressor genes. Increasing studies have shown that DNA methylation is closely related to several physiological and pathological processes including HSC activation and liver fibrosis. This review aimed to discuss the mechanism of DNA methylation in the pathogenesis of liver fibrosis, explore DNA methylation inhibitors as potential therapies for liver fibrosis, and provide new insights on the prevention and clinical treatment of liver fibrosis.

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Section: Liver Fibrosis-related Genes and Dna Methylationmentioning

confidence: 62%

Section: Liver Fibrosis-related Genes and Dna Methylationmentioning

confidence: 99%

Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis

et al. 2023

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“…Therefore, downregulation of FTO mediated the upregulation of m 6 A modification may become a valid method to inhibit HSCs activation. m 6 A is the most prevalent posttranscriptional modification of mRNA, occurring at approximately three to five sites per mRNA in mammals [21]. Accumulating studies have indicated that m 6 A modification participates the autophagy activation by modifying ATGs and further regulates a variety of physiological and pathological processes [22].…”

Section: Discussionmentioning

confidence: 99%

FTO-mediated m6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis

Huang,

Zhang,

Ren

et al. 2024

Preprint

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The activation of hepatic stellate cells (HSCs) is the central link in the occurrence and development of liver fibrosis. Our previous studies showed that autophagy promotes HSCs activation and ultimately accelerates liver fibrosis. Unc-51-like autophagy activating kinase 1 (ULK1) is an autophagic initiator in mammals and N6-methyladenosine (m6A) modification is closely related to autophagy. In this study, we find that m6A demethylase fat mass and obesity-associated protein (FTO) is upregulated during HSCs activation and bile duct ligation (BDL)-induced hepatic fibrosis, which is the m6A methylase with the most significant difference in expression. Importantly, we identify that FTO overexpression aggravates HSCs activation and hepatic fibrosis via autophagy. Mechanistically, compared with other autophagy-related genes, ULK1 is the target of FTO due to FTO mainly mediates the m6A demethylation of ULK1 and upregulates its expression, thereby enhancing autophagy and activation of HSCs. Noteworthy, m6A reader YTH domain-containing protein 2 (YTHDC2) decreases ULK1 mRNA level via recognizing the m6A binding site and ultimately inhibits autophagy and activation of HSCs. Taken together, our findings highlight m6A-dependent ULK1 as an essential regulator of HSCs autophagy and reveal ULK1 as a novel potential therapeutic target for hepatic fibrosis treatment.

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“…ALKBH5 is down‐regulated in liver tissues of a CCL4‐induced mouse liver fibrosis model and in TGF‐β‐stimulated activated HSC in vitro, whereas high expression of ALKBH5 ameliorates liver fibrosis and inhibits HSC activation. 27 The distinct outcomes are largely attributable to differences in experimental intervention conditions, resulting in different expression status of ALKBH5. Recent findings demonstrate that hypoxia as well as some epigenetic regulators, transcription factors and noncoding RNAs are involved in regulating the abnormal expression of ALKBH5.…”

Section: Discussionmentioning

confidence: 99%

“…However, ALKBH5 responded differently to irradiated and non‐irradiated conditions. ALKBH5 is down‐regulated in liver tissues of a CCL4‐induced mouse liver fibrosis model and in TGF‐β‐stimulated activated HSC in vitro, whereas high expression of ALKBH5 ameliorates liver fibrosis and inhibits HSC activation 27 . The distinct outcomes are largely attributable to differences in experimental intervention conditions, resulting in different expression status of ALKBH5.…”

Section: Discussionmentioning

confidence: 99%

ALKBH5‐mediated m⁶A demethylation of TIRAP mRNA promotes radiation‐induced liver fibrosis and decreases radiosensitivity of hepatocellular carcinoma

Chen

Zhou

Deng

et al. 2023

Clinical & Translational Med

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Background Radiation‐induced hepatic stellate cell (HSC) activation promotes radiation‐induced liver fibrosis (RILF), a complication for hepatocellular carcinoma (HCC) radiotherapy. The demethylase alpha‐ketoglutarate‐dependent dioxygenase alkB homolog 5 (ALKBH5) decreases N6‐methyladenylate methylation (m 6 A) modification of RNA, while its role in regulating RILF pathogenesis and HCC radiosensitivity remains unknown. Methods Methylated RNA immunoprecipitation sequencing (MeRIP‐seq) and RNA‐sequencing (RNA‐seq) were used to screen target genes regulated by ALKBH5. HSC with altered ALKBH5 expression was used to assess irradiation‐induced HSC activation and the effect of HSC on recruitment and polarisation of monocytes. Key cytokines in medium from irradiated HSC‐educated monocytes were identified by cytokine array detection. The effects of blocking ALKBH5 and key cytokines on RILF and HCC radiosensitivity were also evaluated. Results Radiation‐induced ALKBH5 expression in HSC mediated m 6 A demethylation of toll‐interleukin 1 receptor domain containing adaptor protein (TIRAP) mRNA and activated its downstream NF‐κB and JNK/Smad2 pathways to promote HSC activation. Additionally, ALKBH5 regulated CCL5 secretion by irradiated HSC to promote monocyte recruitment and M2 macrophage polarisation. Notably, polarised monocytes secreted CCL20 to up‐regulate ALKBH5 expression in HSC, and reduce HCC radiosensitivity by activating ALKBH5/TIRAP axis in HCC cells. ALKBH5 knockdown‐combined CCR6 (CCL20 receptor) inhibitor significantly alleviated RILF and improved HCC radiosensitivity in mice. HCC patients with high ALKBH5 and TIRAP expression were prone to radiation‐induced liver injury and poor tumour response to radiotherapy. Conclusions Collectively, irradiation up‐regulates ALKBH5 in HSC to mediate monocyte recruitment and M2 polarisation and form positive feedback to promote RILF and reduce HCC radiosensitivity. The dual roles of ALKBH5 as a microenvironmental regulator and radiosensitisation target provide new ideas for RILF prevention and radiosensitisation of HCC.

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ALKBH5 ameliorated liver fibrosis and suppressed HSCs activation via triggering PTCH1 activation in an m6A dependent manner

Cited by 27 publications

References 32 publications

Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis

Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis

FTO-mediated m6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis

ALKBH5‐mediated m⁶A demethylation of TIRAP mRNA promotes radiation‐induced liver fibrosis and decreases radiosensitivity of hepatocellular carcinoma

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ALKBH5 ameliorated liver fibrosis and suppressed HSCs activation via triggering PTCH1 activation in an m6A dependent manner

Cited by 27 publications

References 32 publications

Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis

Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis

FTO-mediated m6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis

ALKBH5‐mediated m6A demethylation of TIRAP mRNA promotes radiation‐induced liver fibrosis and decreases radiosensitivity of hepatocellular carcinoma

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ALKBH5‐mediated m⁶A demethylation of TIRAP mRNA promotes radiation‐induced liver fibrosis and decreases radiosensitivity of hepatocellular carcinoma