Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma

Hao, Liyuan; Guo, Yinglin; Peng, Qing; Zhang, Zhiqin; Ji, Jingmin; Liu, Yiwei; Xue, Yu; Li, Caige; Zheng, Kangning; Shi, Xinli

doi:10.1016/j.phymed.2021.153913

Cited by 19 publications

(17 citation statements)

References 44 publications

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“…Hepatocyte‐specific Yap1 knockout mice ( Yap1 Flox/Flox ; albumin‐Cre , marked as Yap1 LKO ) and control mice ( Yap1 Flox/Flox , marked as Yap1 Flox ) were constructed and identified by Cyagen Biosciences (Guangzhou, China) 20 . Four‐week‐old male mice were intraperitoneally injected with APAP (300 mg/kg body weight) for 24 h. AKK group was given activated‐ A. muciniphila (1 × 10 8 CFU/ml, 0.1 ml/mice, dissolved in sterile water), and the NS group mice were given 0.9% saline (0.1 ml/mice).…”

Section: Methodsmentioning

confidence: 99%

Wolfberry enhanced the abundance of Akkermansia muciniphila by YAP1 in mice with acetaminophen‐induced liver injury

et al. 2022

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Drug‐induced liver injury (DILI) by acetaminophen (APAP) was one of the most challenging liver diseases. Wolfberry (Lycium barbarum L.), a traditional Chinese medicinal material and food supplement, has a potential effect on increasing the abundance of Akkermansia muciniphila (A. muciniphila) in mice colons. However, the effect and mechanism of wolfberry remain unclear in APAP‐induced DILI. In this study, wolfberry promoted the proliferation of activated‐A. muciniphila in vitro and in vivo. For the first time, we detected that the activated‐A. muciniphila but not the killed‐A. muciniphila increased the expression level of Yes‐associated protein 1 (YAP1) in the liver and alleviated liver injury in APAP‐induced DILI mice. Mechanically, A. muciniphila improved the intestinal mucosal barrier and reduced lipopolysaccharide (LPS) content in the liver, leading to the increased expression level of YAP1. Furthermore, wolfberry increased the A. muciniphila abundance in the colon and YAP1 expression in the liver from APAP‐induced DILI mice, which promoted the recovery of APAP‐induced liver injury. Meanwhile, wolfberry combination with A. muciniphila synergistically increased AKK abundance and YAP1 expression in the liver. Our research provides an innovative strategy to improve DILI.

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Section: Methodsmentioning

confidence: 99%

Wolfberry enhanced the abundance of Akkermansia muciniphila by YAP1 in mice with acetaminophen‐induced liver injury

et al. 2022

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“…A comprehensive analysis of transcriptome and metabonomic in our study shows that YAP1 knockdown inhibits the proliferation and metastasis mainly by regulating lipid metabolism in HCC cells ( 147 ). Our previous studies also show that YAP1 knockdown/knockout reduces LD deposition and the membrane protein perilipin2 (PLIN2) expression on the surface of LDs in HCC cells ( 35 , 148 ). Down-regulation of YAP1 reduces LD accumulation in mice with non-alcoholic fatty liver disease and inhibits the proliferation and invasion of HCC cells ( 149 ).…”

Section: Yap1 Is Extensively Involved In the Metabolic Reprogramming ...mentioning

confidence: 78%

“…Our previous research found that YAP1 suppression (knockdown or chemical inhibition) enhanced the effectiveness of anti-PD-1 immunotherapy in mice with liver tumors ( 34 ). This effect related to the suppression of immunosuppressive TME, the balance of intestinal microorganisms, and the homeostasis of lipid metabolism in HCC cells dependent on YAP1 ( 35 – 37 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting YAP1 to improve the efficacy of immune checkpoint inhibitors in liver cancer: mechanism and strategy

Gao,

Gong,

et al. 2024

Front. Immunol.

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Liver cancer is the third leading of tumor death, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors (ICIs) are yielding much for sufferers to hope for patients, but only some patients with advanced liver tumor respond. Recent research showed that tumor microenvironment (TME) is critical for the effectiveness of ICIs in advanced liver tumor. Meanwhile, metabolic reprogramming of liver tumor leads to immunosuppression in TME. These suggest that regulating the abnormal metabolism of liver tumor cells and firing up TME to turn “cold tumor” into “hot tumor” are potential strategies to improve the therapeutic effect of ICIs in liver tumor. Previous studies have found that YAP1 is a potential target to improve the efficacy of anti-PD-1 in HCC. Here, we review that YAP1 promotes immunosuppression of TME, mainly due to the overstimulation of cytokines in TME by YAP1. Subsequently, we studied the effects of YAP1 on metabolic reprogramming in liver tumor cells, including glycolysis, gluconeogenesis, lipid metabolism, arachidonic acid metabolism, and amino acid metabolism. Lastly, we summarized the existing drugs targeting YAP1 in the treatment of liver tumor, including some medicines from natural sources, which have the potential to improve the efficacy of ICIs in the treatment of liver tumor. This review contributed to the application of targeted YAP1 for combined therapy with ICIs in liver tumor patients.

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“…29 We also found that DHA reduced the expression of YAP1 and decreased lipid droplets, enhancing immunotherapy. 41 In addition, our previous study found that DDP promoted the expression of YAP1 and PD-L1 in liver tumor-bearing mice, which may be the mechanism of DDP resistance. 21 Therefore, YAP1 was a potential therapeutic target for liver cancer.…”

Section: Discussionmentioning

confidence: 96%

PD-1/PD-L1 Interaction Upregulates YAP1 Expression in HepG2 Cells Through MAPK/ERK Pathway

Li,

Dai,

Wang

et al. 2023

Natural Product Communications

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Background Antibodies, which target programmed cell death protein-1 (PD-1) or its ligand programmed death ligand-1 (PD-L1), can rescue T cells from an exhausted state and resume their immune response to cancer cells. Clinically, the purpose of blocking the PD-1/PD-L1 signaling pathway is to induce immune cells to play an anti-tumor role. However, the effect of intertumor PD-1/PD-L1 signal blocking on tumor cells remains unclear. Methods HepG2 cells were treated with DHA, IFN-γ, BSA, DDP, PD-1-Fc (1 μg/ml), IgG-Fc, nivolumab, or human IgG for 24 h, respectively. GEPIA, cBioPortal, and TIMER databases were used to analyze the correlation between YAP1, PD-1, and PD-L1 and ERK, ERK-5, JNK, and p38. Western blot was used to detect the expression of YAP1 and p-ERK. Results GEPIA, cBioPortal, and TIMER databases analysis showed that YAP1 was positively correlated with ERK. After HepG2 cells were treated with PD98059 (ERK inhibitor), the expression of YAP1 was decreased. In this study, we investigated the inhibitory effect of PD98059 on PD-1/PD-L1 signaling. Our study found that PD-1-Fc (PD-1 fusion protein) promoted the expression of p-ERK/ERK and YAP1 in HepG2 cells. In contrast, nivolumab (PD-1 blocking antibody) reduced the expression of p-ERK/ERK and YAP1 in IFN-γ-pretreated HepG2 cells. In addition, the application of DHA also inhibited the expression of p-ERK/ERK to inhibit YAP1. Furthermore, treatment of HepG2 cells with DHA alone or DHA combined with cisplatin (DDP) both inhibited the expression of p-ERK/ERK and YAP1. Conclusions These results suggested that PD-1/PD-L1 interactions between tumor cells could promote the expression of ERK or YAP1 within tumors. Moreover, the conduction of PD-1/PD-L1 could be reversed using ERK inhibitors.

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Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma

Cited by 19 publications

References 44 publications

Wolfberry enhanced the abundance of Akkermansia muciniphila by YAP1 in mice with acetaminophen‐induced liver injury

Wolfberry enhanced the abundance of Akkermansia muciniphila by YAP1 in mice with acetaminophen‐induced liver injury

Targeting YAP1 to improve the efficacy of immune checkpoint inhibitors in liver cancer: mechanism and strategy

PD-1/PD-L1 Interaction Upregulates YAP1 Expression in HepG2 Cells Through MAPK/ERK Pathway

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