Lactate Dehydrogenase Inhibition Protects against Hepatic Fibrosis by Regulating Metabolic Reprogramming of Hepatic Stellate Cells

Hepatic stellate cells (HSCs) activation results in liver fibrosis. When HSCs are activated, metabolism is reprogrammed. However, metabolic alteration in HSCs activation has not been sufficiently addressed. This study aims to investigate the role of lactate dehydrogenase (LDH) inhibition in HSCs activation with an emphasis on the metabolic reprogramming. Mice were subjected to carbon tetrachloride (CCl₄) to induce liver injury. In addition, the primary HSCs were isolated for mechanism investigation. Our study demonstrated that LDH inhibition impaired HSCs activation through suppressing the enhanced glycolysis by blocking nicotinamide adenine dinucleotide (NAD⁺) regeneration. Meanwhile, LDH inhibition also impeded the glutamine metabolism through the lactic acid/histone deacetylase (HDAC)/histone acetylation/cellular-myelocytomatosis viral oncogene (c-Myc) signaling pathway. Our findings demonstrated that LDH inhibition is a potential target for liver fibrosis treatment, which provides new insight into the pathogenesis of liver fibrosis from the aspect of metabolic reprogramming, contributing to the design of a novel therapeutic strategy in the management of liver fibrosis.