Fine-tuning of regulatory T cells is indispensable for the metabolic steatosis-related hepatocellular carcinoma: A review

Abstract

The majority of chronic hepatic diseases are caused by nutritional imbalance. These nutritional inequities include excessive intake of alcohol and fat, which causes alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), respectively. The pathogenesis of hepatic diseases is mainly dependent on oxidative stress, autophagy, DNA damage, and gut microbiota and their metabolites. These factors influence the normal physiology of the liver and impact the hepatic microenvironment. The hepatic microenvironment contains several immune cells and inflammatory cytokines which interact with each other and contribute to the progression of chronic hepatic diseases. Among these immune cells, Foxp3+ CD4+ regulatory T cells (Tregs) are the crucial subset of CD4+ T cells that create an immunosuppressive environment. This review emphasizes the function of Tregs in the pathogenesis of ALD and NAFLD and their role in the progression of NAFLD-associated hepatocellular carcinoma (HCC). Briefly, Tregs establish an immunosuppressive landscape in the liver by interacting with the innate immune cells and gut microbiota and their metabolites. Meanwhile, with the advancement of steatosis, these Tregs inhibit the proliferation, activation and functions of other cytotoxic T cells and support the progression of simple steatosis to HCC. Briefly, it can be suggested that targeting Tregs can act as a favourable prognostic indicator by modulating steatosis and insulin resistance during the pathogenesis of hepatic steatosis and NAFLD-associated HCC.

Identification and Evaluation of Hub Long Noncoding RNAs and mRNAs in High Fat Diet Induced Liver Steatosis

“…In the blue module, Flywch1 was the core lncRNA connected to three hub genes (Foxp3, Mef2c, and Serpine1). Foxp3 has been reported to be involved in the development of NAFLD through the regulation of lipid metabolism and the inflammatory microenvironment [ 52 , 53 ]. Additionally, Mef2c has been connected with inflammatory diseases in humans and animals [ 54 , 55 ].…”

Τ cell-mediated adaptive immunity in the transition from metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma

“…On the other hand, T-regulatory cells (Tregs) might have opposing contributions to MASH-induced HCC. While their presence is deemed beneficial in humans with viral HCC ( Sharma et al, 2015 ), murine studies suggest that an imbalanced metabolic phenotype of Tregs can exacerbate the loss of immunosurveillance, promoting the tumorigenic shift of MASH ( Wang et al, 2021 ; Riaz et al, 2022 ). In addition, distinct CD4+ T cell subsets, such as Th1 and Th17 helper T cells, which contribute to MASLD to MASH progression ( Her et al, 2020 ), might have a critical role in the MASH to HCC transition.…”

“…Additionally, novel interactions can emerge, such as those between cancer-associated fibroblasts (CAFs) and hepatic immune populations ( Ying et al, 2023 ). While the stem cell milieu contributes to increased proliferative capacity and stemness in the HCC liver ( Zhu et al, 2021b ; Yu et al, 2023 ), current research highlights a strong link between the MASH-induced HCC phenotype and the biological fonts of immune tolerance, suppression, and surveillance ( Peiseler and Tacke, 2021 ; Riaz et al, 2022 ; Pinter et al, 2023 ). To date, experimental animal models are the gold standard in the MASH-induced HCC research field ( Febbraio et al, 2019 ; Gallage et al, 2022 ).…”

Salvianolic acid B from Salvia miltiorrhiza bunge: A potential antitumor agent

“…Hepatocellular carcinoma is a major cause of mortality ( Riaz et al, 2022 ; Xia et al, 2022 ), and hepatitis B and C viruses are major contributors to hepatocellular carcinoma. Unfortunately, most HCC patients are diagnosed at a late stage, thus surgery is not a treatment option ( Khafaga et al, 2022 ; Wei et al, 2022 ).…”