Mechanism of ASK1 involvement in liver diseases and related potential therapeutic targets: A critical pathway molecule worth investigating

Chen, Qi; Guo, Jiayu; Qiu, Tao; Zhou, Jiangqiao

doi:10.1111/jgh.16087

Cited by 4 publications

(4 citation statements)

References 78 publications

(148 reference statements)

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“…ASK1, functioning as a MAPK kinase kinase, has been reported to phosphorylate JNK, thereby regulating cell apoptosis and various cellular physiological and pathological functions . This underscores the key role of ASK1 in NASH, and inhibiting the ASK1 pathway along with its downstream JNK signaling pathway emerges as a promising strategy to inhibit NASH. , In previous studies, the ASK1 signaling pathway has been demonstrated to activate in different in vivo and in vitro NASH models accompanied by a significantly increase in ASK1 phosphorylation . TRAFs, including TRAF2 and TRAF6, have been shown to interact with ASK1 and activate under different stimuli. , We have identified for the first time that lycopene can inhibit the phosphorylation of ASK1 in both in vivo and in vitro models.…”

Section: Discussionmentioning

confidence: 95%

“…54 This underscores the key role of ASK1 in NASH, and inhibiting the ASK1 pathway along with its downstream JNK signaling pathway emerges as a promising strategy to inhibit NASH. 16,55 In previous studies, the ASK1 signaling pathway has been demonstrated to activate in different in vivo and in vitro NASH models accompanied by a significantly increase in ASK1 phosphorylation. 55 TRAFs, including TRAF2 and TRAF6, have been shown to interact with ASK1 and activate under different stimuli.…”

Section: ■ Discussionmentioning

confidence: 99%

“…16,55 In previous studies, the ASK1 signaling pathway has been demonstrated to activate in different in vivo and in vitro NASH models accompanied by a significantly increase in ASK1 phosphorylation. 55 TRAFs, including TRAF2 and TRAF6, have been shown to interact with ASK1 and activate under different stimuli. 56,57 We have identified for the first time that lycopene can inhibit the phosphorylation of ASK1 in both in vivo and in vitro models.…”

Section: ■ Discussionmentioning

confidence: 99%

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Lycopene Alleviates Endoplasmic Reticulum Stress in Steatohepatitis through Inhibition of the ASK1–JNK Signaling Pathway

Song,

Sun,

Liu

et al. 2024

J. Agric. Food Chem.

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Lycopene has been proven to alleviate nonalcoholic steatohepatitis (NASH), but the precise mechanisms are inadequately elucidated. In this study, we found a previously unknown regulatory effect of lycopene on the apoptosis signalregulating kinase 1 (ASK1) signaling pathway in both in vivo and in vitro models. Lycopene supplementation (3 and 6 mg/kg/day) exhibited a significant reduction in lipid accumulation, inflammation, and fibrosis of the liver in mice fed with a high-fat/highcholesterol diet or a methionine-choline-deficient diet. RNA sequencing uncovered that the mitogen-activated protein kinases signaling pathway, which is closely associated with inflammation and endoplasmic reticulum (ER) stress, was significantly downregulated by lycopene. Furthermore, we found lycopene ameliorated ER swelling and decreased the expression levels of ER stress markers (i.e., immunoglobulin heavy chain binding protein, C/EBP homologous protein, and X-box binding protein 1s). Especially, the inositol-requiring enzyme 1α involved in the ASK1 phosphorylation was inhibited by lycopene, resulting in the decline of the subsequent c-Jun N-terminal kinase (JNK) signaling cascade. ASK1 inhibitor DQOP-1 eliminated the lycopeneinduced inhibition of the ASK1−JNK pathway in oleic acid and palmitic acid-induced HepG2 cells. Molecular docking further indicated hydrophobic interactions between lycopene and ASK1. Collectively, our research indicates that lycopene can alleviate ER stress and attenuate inflammation cascades and lipid accumulation by inhibiting the ASK1−JNK pathway.

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Section: Discussionmentioning

confidence: 95%

Section: ■ Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

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Lycopene Alleviates Endoplasmic Reticulum Stress in Steatohepatitis through Inhibition of the ASK1–JNK Signaling Pathway

Song,

Sun,

Liu

et al. 2024

J. Agric. Food Chem.

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“…Following activation, ASK1 phosphorylates and activates downstream targets, particularly the mitogen-activated protein kinase (MAPK) kinase kinase family members like MKK4 and MKK7. These, in turn, stimulate the c-Jun N-terminal kinase (JNK)/p38 signaling pathways, ultimately triggering the activation of transcription factors responsible for regulating genes associated with stress responses, cell proliferation, and apoptosis [ 9 ]. Posttranslational modifications regulate the kinase activity of ASK1.…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular SETDB1 Regulates Hepatic Ischemia-Reperfusion Injury through Targeting Lysine Methylation of ASK1 Signal

Xia,

Wang,

Chen

et al. 2023

Research

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Background: Hepatic ischemia-reperfusion injury (HIRI) stands as an unavoidable complication arising from liver surgery, profoundly intertwined with its prognosis. The role of lysine methyltransferase SET domain bifurcated 1 (SETDB1) in HIRI remains elusive, despite its confirmation as a potential therapeutic target for diverse diseases. Here, we investigated the mechanism by which SETDB1 regulated HIRI. Methods: RNA sequencing data were used to identify the expression and potential targets of SETDB1 through bioinformatics analysis. To elucidate the impact of SETDB1 on HIRI, both an in vivo model of HIRI in mice and an in vitro model of hepatocyte hypoxia/reoxygenation were established. Biochemical and histological analyses were used to investigate the influence of SETDB1 on liver damage mediated by HIRI. Chromatin immunoprecipitation and coimmunoprecipitation were implemented to explore the in-depth mechanism of SETDB1 regulating HIRI. Results: We confirmed that hepatocellular SETDB1 was up-regulated during HIRI and had a close correlation with HIRI-related inflammation and apoptosis. Moreover, inhibition of SETDB1 could mitigate HIRI-induced liver damage, inflammation, and apoptosis. Through our comprehensive mechanistic investigation, we revealed that SETDB1 interacts with apoptosis-signal-regulating kinase 1 (ASK1) and facilitates the methylation of its lysine residues. Inhibition of SETDB1 resulted in reduced phosphorylation of ASK1, leading to a marked suppression of downstream c-Jun N-terminal kinase (JNK)/p38 signaling pathway activation. The therapeutic effect on inflammation and apoptosis achieved through SETDB1 inhibition was nullified by the restoration of JNK/p38 signaling activation through ASK1 overexpression. Conclusions: The findings from our study indicate that SETDB1 mediates lysine methylation of ASK1 and modulates the activation of the ASK1–JNK/p38 pathway, thus involved in HIRI-induced inflammation and apoptosis. These results suggest that SETDB1 holds promise as a potential therapeutic target for mitigating HIRI.

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SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway

Shen,

Lai,

et al. 2024

Inflamm. Res.

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Background Microglia, the main innate immune cells in the central nervous system, are key drivers of neuroinflammation, which plays a crucial role in the pathogenesis of neurodegenerative diseases. The Sin3/histone deacetylase (HDAC) complex, a highly conserved multiprotein co-repressor complex, primarily performs transcriptional repression via deacetylase activity; however, the function of SDS3, which maintains the integrity of the complex, in microglia remains unclear. Methods To uncover the regulatory role of the transcriptional co-repressor SDS3 in microglial inflammation, we used chromatin immunoprecipitation to identify SDS3 target genes and combined with transcriptomics and proteomics analysis to explore expression changes in cells following SDS3 knocking down. Subsequently, we validated our findings through experimental assays. Results Our analysis revealed that SDS3 modulates the expression of the upstream kinase ASK1 of the p38 MAPK pathway, thus regulating the activation of signaling pathways and ultimately influencing inflammation. Conclusions Our findings provide important evidence of the contributions of SDS3 toward microglial inflammation and offer new insights into the regulatory mechanisms of microglial inflammatory responses.

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Mechanism of ASK1 involvement in liver diseases and related potential therapeutic targets: A critical pathway molecule worth investigating

Cited by 4 publications

References 78 publications

Lycopene Alleviates Endoplasmic Reticulum Stress in Steatohepatitis through Inhibition of the ASK1–JNK Signaling Pathway

Lycopene Alleviates Endoplasmic Reticulum Stress in Steatohepatitis through Inhibition of the ASK1–JNK Signaling Pathway

Hepatocellular SETDB1 Regulates Hepatic Ischemia-Reperfusion Injury through Targeting Lysine Methylation of ASK1 Signal

SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway

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