Mitochondrial damage-associated molecular patterns (mito-DAMPs): Determinants of hepatopathy progression and therapeutic implications

Liver diseases, as the primary representative disorders of the digestive tract, encompass metabolic dysfunction-associated steatotic liver disease (MASLD), liver fibrosis, and malignant liver or gallbladder cancers and pose a significant health challenge to millions of individuals worldwide. Meanwhile, to make matters worse, the incidence of MASLD, which can progress to end-stage liver disease, has gradually increased in recent years due to shifts in dietary practices and lifestyle choices. In the context of various liver diseases, endogenous danger signals released from damaged or dying cells, known as damage-associated molecular patterns (DAMPs), can be recognized by the innate immune system through pattern recognition receptors. This recognition subsequently leads to the recruitment of immune cells and the activation of an inflammatory cascade. Recently, mitochondria have garnered significant attention as a novel source of DAMPs, namely mito-DAMPs. Under stress conditions, various pro-inflammatory mediators, previously thought to play a crucial role in the pathogenesis of liver disease, are released from mitochondria, including mitochondrial DNA, reactive oxygen species, cytochrome c, adenosine triphosphate, cardiolipin and carbamoyl phosphate synthetase 1. Here, we emphasize the significance of these novel mito-DAMPs in the initiation and progression of various liver diseases and discuss the interplay among these molecules under different pathological environment. Our aim is to explore potential therapeutic targets and strategies in drug development that can be employed to combat liver diseases.