Mitochondrial dysfunction in MASH: Focusing on chronic inflammation and intercellular communication

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition closely linked to metabolic dysregulation. In its progressive stage, metabolic dysfunction-associated steatohepatitis (MASH), hepatocytes face pathological insults including lipotoxicity and inflammatory cell infiltration. Sustained exposure to these stressors severely disrupts hepatocyte mitochondrial homeostasis, culminating in mitochondrial dysfunction. Crucially, mitochondrial dysfunction is intimately associated with chronic inflammation. After injury, mitochondria produce large amounts of mitochondrial reactive oxygen species (mtROS) or release mitochondrial damage-associated molecules that act as signaling molecules to recruit and activate inflammatory cells, such as neutrophils. Activated neutrophils release neutrophil extracellular traps (NETs), which exacerbate liver inflammation, driving MASH progression towards liver cancer. Despite advances in the understanding of MASLD pathophysiology, challenges remain in identifying relation between mitochondrial dysfunction and intrahepatic inflammation. Intercellular communication, primarily mediated by extracellular vesicles (EVs), plays a pivotal role in this pathology. EVs transport diverse bioactive cargo from donor to recipient cells, modulating various pathophysiological processes. This review synthesizes current literature on mitochondrial dysfunction and chronic inflammation in MASH/MASLD, examines the critical role of intrahepatic intercellular communication, particularly via EVs, and highlights targeting mitochondria as a promising therapeutic strategy for MASH.