2023
DOI: 10.1097/hep.0000000000000401
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Targeting senescent hepatocytes using the thrombomodulin-PAR1 inhibitor vorapaxar ameliorates NAFLD progression

Abstract: Background and Aims: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Senescing cells upregulate thrombomodulin–protease-activated receptor-1 (THBD-PAR1) signaling to remain viable. Vorapaxar blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibro… Show more

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Cited by 9 publications
(4 citation statements)
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“…We found that the binding energies of the 6 small molecules and the 6 hub genes were all less than −7 kcal/mol, which was consistent with the results of AmAT7-3 (Supplementary Material Table S1 ). We also used 6 hub genes for molecular docking with their targeted inhibitors ( PDGFRB and Ripretinib [ 23 ], KIT and Imatinib [ 24 ], FGF1 and PD161570 [ 25 ], GLI1 and GANT61 [ 26 ], F2R and Vorapaxar [ 27 ], HIF1A and PX478 [ 28 ], Supplementary Material Fig. S1 ), and the results showed that Polyphyllin Ⅲ had similar binding energy with the inhibitors, confirming that Polyphyllin had good biological activity (Supplementary Material Table S2 ).…”
Section: Resultsmentioning
confidence: 99%
“…We found that the binding energies of the 6 small molecules and the 6 hub genes were all less than −7 kcal/mol, which was consistent with the results of AmAT7-3 (Supplementary Material Table S1 ). We also used 6 hub genes for molecular docking with their targeted inhibitors ( PDGFRB and Ripretinib [ 23 ], KIT and Imatinib [ 24 ], FGF1 and PD161570 [ 25 ], GLI1 and GANT61 [ 26 ], F2R and Vorapaxar [ 27 ], HIF1A and PX478 [ 28 ], Supplementary Material Fig. S1 ), and the results showed that Polyphyllin Ⅲ had similar binding energy with the inhibitors, confirming that Polyphyllin had good biological activity (Supplementary Material Table S2 ).…”
Section: Resultsmentioning
confidence: 99%
“…The recent discovery that adult hepatocytes themselves require Hedgehog pathway activity to remain metabolically nimble and avoid senescence suggests that loss of Hedgehog pathway activity in hepatocytes may be one of the initiating events for liver repair 16,21 . This concept is supported by evidence that senescing hepatocytes emit Hedgehog ligands and other signals that mobilize both immune cells to clear the senescent hepatocytes and activate progenitor cells to become their replacements 36 . Extension of this logic predicts that the exuberance of progenitor outgrowth and other wound healing responses (e.g., inflammation, fibrosis, angiogenesis) will parallel the level of senescent cell accumulation and continue until the burden of senescent hepatocytes is dissipated (Figure 3).…”
Section: Accepted Manuscriptmentioning
confidence: 95%
“…16,21 This concept is supported by evidence that senescing hepatocytes emit Hedgehog ligands and other signals that mobilize both immune cells to clear the senescent hepatocytes and activate progenitor cells to become their replacements. 36 Extension of this logic predicts that the exuberance of progenitor outgrowth and other wound healing responses (e.g., inflammation, fibrosis, angiogenesis) will parallel the level of senescent cell accumulation and continue until the burden of senescent hepatocytes is dissipated (►Fig. 3).…”
Section: Dysregulation Of Hedgehog Signaling In Liver Diseasementioning
confidence: 99%
“…By inhibiting thrombomodulin (THBD) signaling, a key pathway in the fate of senescent cells by vorapaxar, it is possible to eliminate senescent cells during the hepatic fibrosis process and maintain liver homeostasis [ 116 ]. Moreover, using the vorapaxar also can ameliorate nonalcoholic fatty liver disease progression by targeting the senescent hepatocytes [ 117 ]. Furthermore, chimeric antigen receptor (CAR)T cells targeting the urokinase-type plasminogen activator receptor (uPAR) can serve as senolytic drugs to eliminate senescent cells and reduce CCl4-induced or nonalcoholic steatohepatitis-induced liver fibrosis [ 118 ].…”
Section: Strategies Of Ameliorating Aging-related Immunosenescencementioning
confidence: 99%