Sirtuin 1 in regulating the p53/glutathione peroxidase 4/gasdermin D axis in acute liver failure

In this editorial,we comment on the article by Zhou et al.The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1(SIRT1)activation in acute liver failure(ALF).ALF is characterized by a sudden and severe liver injury resulting in significant hepatocyte damage,often posing a high risk of mortality.The predominant form of hepatic cell death in ALF involves apoptosis,ferroptosis,autophagy,pyroptosis,and necroptosis.Glutathione peroxidase 4(GPX4)inhibition sensitizes the cell to ferroptosis and triggers cell death,while Gasdermin D(GSDMD)is a mediator of pyroptosis.The study showed that ferroptosis and pyroptosis in ALF are regulated by blocking the p53/GPX4/GSDMD pathway,bridging the gap between the two processes.The inhibition of p53 elevates the levels of GPX4,reducing the levels of inflammatory and liver injury markers,ferroptotic events,and GSDMDN protein levels.Reduced p53 expression and increased GPX4 on deletion of GSDMD indicated ferroptosis and pyroptosis interaction.SIRT1 is a NAD-dependent deacetylase,and its activation attenuates liver injury and inflammation,accompanied by reduced ferroptosis and pyroptosis-related proteins in ALF.SIRT1 activation also inhibits the p53/GPX4/GSDMD axis by inducing p53 acetylation,attenuating LPS/D-GalN-induced ALF.

Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma:Experimental and clinical scenarios

Hepatocellular carcinoma(HCC)is the most common type of liver cancer worldwide.Viral hepatitis is a significant risk factor for HCC,although metabolic syndrome and diabetes are more frequently associated with the HCC.With increasing prevalence,there is expected to be>1 million cases annually by 2025.Therefore,there is an urgent need to establish potential therapeutic targets to cure this disease.Peroxisome-proliferator-activated receptor gamma(PPARγ)is a ligand-activated transcription factor that plays a crucial role in the pathophysiology of HCC.Many synthetic agonists of PPARγsuppress HCC in experimental studies and clinical trials.These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC.However,some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy.Thus natural PPARγagonists can be an alternative to exploit this potential target for HCC treatment.In this review,the regulatory role of PPARγin the pathogenesis of HCC is elucidated.Furthermore,the experimental and clinical scenario of both synthetic and natural PPARγagonists against HCC is discussed.Most of the available literature advocates PPARγas a potential therapeutic target for the treatment of HCC.