Center for Drug Discovery, BRIC-Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, India; Department of Chemistry, Faculty of Applied and Basic Sciences, SGT University, Gurugram 122505, India.
Center for Drug Discovery, BRIC-Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, India.
Pharmacol Res. 2024 Oct;208:107375. doi: 10.1016/j.phrs.2024.107375. Epub 2024 Aug 30.
The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) is a growing concern for the high incidence rate of hepatocellular carcinoma (HCC) globally. The progression of NAFLD to HCC is heterogeneous and non-linear, involving intermediate stages of non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. There is a high unmet clinical need for appropriate diagnostic, prognostic, and therapeutic options to tackle this emerging epidemic. Unfortunately, at present, there is no validated marker to identify the risk of developing HCC in patients suffering from NAFLD or NASH. Additionally, the current treatment protocols for HCC don't differentiate between viral infection or NAFLD-specific etiology of the HCC and have a limited success rate. The mammalian target of rapamycin complex 1 (mTORc1) is an important protein involved in many vital cellular processes like lipid metabolism, glucose homeostasis, and inflammation. These cellular processes are highly implicated in NAFLD and its progression to severe liver manifestations. Additionally, hyperactivation of mTORc1 is known to promote cell proliferation, which can contribute to the genesis and progression of tumors. Many mTORc1 inhibitors are being evaluated for different types of cancers under various phases of clinical trials. This paper deliberates on the strong pathological implication of the mTORc1 signaling pathway in NAFLD and its progression to NASH and HCC and advocates for a systematic investigation of known mTORc1 inhibitors in suitable pre-clinical models of HCC having NAFLD/NASH-specific etiology.
非酒精性脂肪性肝病（NAFLD）的患病率不断上升，全球肝细胞癌（HCC）的发病率也居高不下，这令人日益担忧。NAFLD 向 HCC 的进展是异质的和非线性的，涉及非酒精性脂肪性肝炎（NASH）、肝纤维化和肝硬化等中间阶段。目前，迫切需要合适的诊断、预后和治疗选择来应对这一新兴的流行疾病，但尚未实现。不幸的是，目前尚无经过验证的标志物来识别患有 NAFLD 或 NASH 的患者发生 HCC 的风险。此外，目前 HCC 的治疗方案无法区分病毒感染或 HCC 的 NAFLD 特异性病因，且成功率有限。哺乳动物雷帕霉素靶蛋白复合物 1（mTORc1）是一种参与许多重要细胞过程的重要蛋白质，如脂质代谢、葡萄糖稳态和炎症。这些细胞过程与 NAFLD 及其向严重肝脏表现的进展密切相关。此外，mTORc1 的过度激活已知可促进细胞增殖，这可能导致肿瘤的发生和进展。许多 mTORc1 抑制剂正在不同的临床试验阶段评估用于不同类型的癌症。本文详细讨论了 mTORc1 信号通路在 NAFLD 及其进展为 NASH 和 HCC 中的强烈病理意义，并主张在具有 NAFLD/NASH 特异性病因的 HCC 的合适临床前模型中系统研究已知的 mTORc1 抑制剂。
