Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Department of Urology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Biomed Pharmacother. 2024 Aug;177:117089. doi: 10.1016/j.biopha.2024.117089. Epub 2024 Jul 6.
Hepatocellular carcinoma (HCC) holds a prominent position among global cancer types. Classically, HCC manifests in individuals with a genetic predisposition when they encounter risk elements, particularly in the context of liver cirrhosis. Peroxisome proliferator-activated receptors (PPARs), which are transcription factors activated by fatty acids, belong to the nuclear hormone receptor superfamily and play a pivotal role in the regulation of energy homeostasis. At present, three distinct subtypes of PPARs have been recognized: PPARα, PPARγ, and PPARβ/δ. They regulate the transcription of genes responsible for cellular development, energy metabolism, inflammation, and differentiation. In recent years, with the rising incidence of HCC, there has been an increasing focus on the mechanisms and roles of PPARs in HCC. PPARα primarily mediates the occurrence and development of HCC by regulating glucose and lipid metabolism, inflammatory responses, and oxidative stress. PPARβ/δ is closely related to the self-renewal ability of liver cancer stem cells (LCSCs) and the formation of the tumor microenvironment. PPARγ not only influences tumor growth by regulating the glucose and lipid metabolism of HCC, but its agonists also have significant clinical significance for the treatment of HCC. Therefore, this review offers an exhaustive examination of the role of the three PPAR subtypes in HCC progression, focusing on their mediation of critical cellular processes such as glucose and lipid metabolism, inflammation, oxidative stress, and other pivotal signaling pathways. At the end of the review, we discuss the merits and drawbacks of existing PPAR-targeted therapeutic strategies and suggest a few alternative combinatorial therapeutic approaches that diverge from conventional methods.
肝细胞癌（HCC）在全球癌症类型中占据重要地位。经典情况下，当个体具有遗传易感性并遇到风险因素时，特别是在肝硬化的背景下，会发生 HCC。过氧化物酶体增殖物激活受体（PPARs）是被脂肪酸激活的转录因子，属于核激素受体超家族，在调节能量稳态方面发挥着关键作用。目前，已经识别出三种不同的 PPAR 亚型：PPARα、PPARγ 和 PPARβ/δ。它们调节负责细胞发育、能量代谢、炎症和分化的基因的转录。近年来，随着 HCC 发病率的上升，人们越来越关注 PPAR 在 HCC 中的机制和作用。PPARα 主要通过调节葡萄糖和脂质代谢、炎症反应和氧化应激来介导 HCC 的发生和发展。PPARβ/δ与肝癌干细胞（LCSCs）的自我更新能力和肿瘤微环境的形成密切相关。PPARγ 不仅通过调节 HCC 的葡萄糖和脂质代谢影响肿瘤生长，其激动剂对 HCC 的治疗也具有重要的临床意义。因此，本综述全面探讨了三种 PPAR 亚型在 HCC 进展中的作用，重点关注它们在葡萄糖和脂质代谢、炎症、氧化应激和其他关键信号通路等关键细胞过程中的介导作用。在综述的最后，我们讨论了现有的 PPAR 靶向治疗策略的优缺点，并提出了一些与传统方法不同的替代组合治疗方法。
