Succinate as a signaling molecule in the mediation of liver diseases

Succinate, one of the intermediates of the tricarboxylic acid (TCA) cycle, plays an essential role in the metabolism of mitochondria and the production of energy, and is considered as a signaling molecule in metabolism as well as in initiation and progression of hepatic diseases. Of note, succinate activates a downstream signaling pathway through GPR91, and elicits a variety of intracellular responses, such as succinylation, production of reactive oxygen species (ROS), stabilization of hypoxia-inducible factor-1 alpha (HIF-1 alpha), and significant impact in cellular metabolism because of the pivotal role in the TCA cycle. Therefore, it is intriguing to deeply elucidate signaling mechanisms of succinate in hepatic fibrosis, metabolic reprogramming in inflammatory or immune responses, as well as carcinogenesis. This manuscript intends to review current understanding of succinate in mediating metabolism, inflammatory and immunologic reactions in liver diseases in order to establish molecular basis for the development of therapeutic strategies.

Automated summary

Succinate, an intermediate of the TCA cycle, is crucial in mitochondrial metabolism, energy production, and is also considered a signaling molecule in metabolism and hepatic diseases. Its downstream signaling pathway through GPR91 leads to various intracellular responses, including succinylation, ROS production, HIF-1 alpha stabilization, and significant impact in cellular metabolism due to its role in the TCA cycle. Understanding the signaling mechanisms of succinate in hepatic fibrosis, metabolic reprogramming, inflammatory or immune responses, and carcinogenesis is of great interest. This review aims to provide the current understanding of succinate in mediating metabolism, inflammatory and immune responses in liver diseases, with the aim of establishing a molecular basis for therapeutic strategies.