J Hepatol (IF=25) Ye Qinghai/Ren Ning/Guo Lei/Li Hui/Hong Mingqi discovered a new strategy to enhance immune checkpoint therapy in hepatocellular carcinoma

iNature Although the advent of effective systemic therapies has revolutionized the treatment of hepatocellular carcinoma (HCC), the prognosis for patients with HCC remains dismal
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Here, the study examines the pathophysiological role of PARG and evaluates the utility of targeted dePARylation in the treatment of HCC
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On February 11, 2022, Ye Qinghai, Ren Ning, Guo Lei, Li Hui, and Hong Mingqi of China Medical University jointly published an online journal of Hepatology (IF=25) entitled "PARG inhibition limits HCC progression and potentiates the efficacy.
of immune checkpoint therapy", which found that high PARG expression is closely related to poor prognosis in HCC
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Hepatocyte-specific PARG deletion significantly impairs liver tumorigenesis
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PARG promotes HCC growth and metastasis through DDB1-dependent regulation of c-Myc
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Specifically, PARG dePARylated DDB1 and thus promoted DDB1 autoubiquitination, thereby stabilizing c-Myc protein in HCC cells
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In HCC patients treated with anti-PD-1-based immunotherapy, PARG downregulation attenuated c-Myc-induced MMR expression and PARG deficiency was associated with favorable prognosis
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Furthermore, PARG inhibitors can synergize with anti-PD-1 antibodies in orthotopic mouse models
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In conclusion, this study finds that PARG acts as an oncogene in HCC by regulating PARG/DDB1/c-Myc signaling and can be used as a biomarker to identify HCC patients who may benefit from anti-PD-1 therapy
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Our findings suggest that combined inhibition of PARG and PD-1 is an effective novel combination strategy for HCC patients
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PARG is the major hydrolase involved in PARylation, acting by degrading nucleopoly (ADP-ribose) (PAR), thereby counteracting the function of PARP enzymes
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Previous work has shown that PARG is involved in a variety of cellular functions, including DNA damage repair, DNA replication, chromatin regulation, transcription, mitochondrial function, and apoptosis
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In recent years, accumulating evidence has also shown that abnormal PARylation catalyzed by PARG has a known tumorigenic effect, and that increased expression of PARG promotes the transformation and invasion of cancer cells
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The pharmacological targeting of PARG has been shown to have promising therapeutic potential in cancer
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However, the physiological role of PARG in HCC progression remains unknown, and its underlying regulatory mechanisms remain to be elucidated
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In this study, the role of PARG in promoting HCC progression and metastasis was explored
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Based on the LC-MS/MS analysis of PARG, DDB1 was identified as a new target of PARG
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Subsequent findings suggest that PARG can act through DDB1 through its downstream oncoprotein c-MYC to drive malignant transformation and progression
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Furthermore, this study found that PARG is associated with mismatch repair (MMR) protein expression, and that PARG deficiency is an indicator of MMR-deficient (dMMR) HCC
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Notably, this study is the first to show that a specific inhibitor targeting PARG is synergistic with PD-1 blockade therapy in a preclinical model of HCC
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In conclusion, this study found that PARG acts as an oncogene in HCC by regulating PARG/DDB1/c-Myc signaling and can be used as a biomarker to identify HCC patients who may benefit from anti-PD-1 therapy
.

Our findings suggest that combined inhibition of PARG and PD-1 is an effective novel combination strategy for HCC patients
.

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