Altered Mitochondrial Function in MASLD: Key Features and Promising Therapeutic Approaches Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), encompasses a range of liver conditions from steatosis to nonalcoholic steatohepatitis (NASH). Its prevalence, especially among patients with metabolic syndrome, highlights its growing global impact. The pathogenesis of MASLD involves metabolic dysregulation, inflammation, oxidative stress, genetic factors, and mitochondrial dysfunction. Recent studies emphasize the critical role of mitochondrial dysfunction in MASLD progression. Therapeutically, enhancing mitochondrial function, along with lifestyle changes and pharmacological interventions targeting mitochondrial processes, has gained interest. The FDA's approval of resmetirom for metabolic-associated steatohepatitis (MASH) with fibrosis marks a significant step. While resmetirom represents progress, further research is essential to fully understand MASLD-related mitochondrial dysfunction. Innovative strategies like gene editing and small-molecule modulators, alongside lifestyle interventions, can potentially improve MASLD treatment. Drug repurposing and new targets will advance MASLD therapy, addressing its increasing global burden. This review aims to provide a better understanding of the role of mitochondrial dysfunction in MASLD and identify more effective preventive and treatment strategies. Mitochondria are essential cellular organelles responsible for energy production through oxidative phosphorylation (OXPHOS). OXPHOS is a metabolic pathway that occurs in the inner mitochondrial membrane and involves a sequence of enzymatic reactions that generate adenosine triphosphate (ATP), the primary energy-supplying molecule for cells. Mitochondrial dysfunction, characterized by impaired OXPHOS, can lead to a range of cellular and physiological abnormalities. Mitochondrial oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and the ability of the cell's antioxidant defenses to neutralize them. Mitochondrial oxidative stress involves a cascade of interconnected mechanisms. Initially, electron leakage from the ETC complexes can engage with molecular oxygen, resulting in the formation of superoxide radicals. Subsequently, these superoxide radicals can undergo enzymatic and non-enzymatic reactions to form other ROS, such as hydrogen peroxide. This process is exacerbated by dysregulation of the ETC or impaired mitochondrial function, which amplifies ROS production. Factors like mitochondrial DNA (mtDNA) mutations, defects in ETC complexes, and loss of membrane potential contribute to this increased ROS generation. Additionally, mitochondria possess various antioxidant defenses to counteract ROS accumulation. Antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, along with non-enzymatic antioxidants like glutathione (GSH), play crucial roles in scavenging ROS and maintaining redox balance. However, when the levels of ROS surpass the capabilities of these defense mechanisms, mitochondrial proteins, lipidsAltered Mitochondrial Function in MASLD: Key Features and Promising Therapeutic Approaches Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), encompasses a range of liver conditions from steatosis to nonalcoholic steatohepatitis (NASH). Its prevalence, especially among patients with metabolic syndrome, highlights its growing global impact. The pathogenesis of MASLD involves metabolic dysregulation, inflammation, oxidative stress, genetic factors, and mitochondrial dysfunction. Recent studies emphasize the critical role of mitochondrial dysfunction in MASLD progression. Therapeutically, enhancing mitochondrial function, along with lifestyle changes and pharmacological interventions targeting mitochondrial processes, has gained interest. The FDA's approval of resmetirom for metabolic-associated steatohepatitis (MASH) with fibrosis marks a significant step. While resmetirom represents progress, further research is essential to fully understand MASLD-related mitochondrial dysfunction. Innovative strategies like gene editing and small-molecule modulators, alongside lifestyle interventions, can potentially improve MASLD treatment. Drug repurposing and new targets will advance MASLD therapy, addressing its increasing global burden. This review aims to provide a better understanding of the role of mitochondrial dysfunction in MASLD and identify more effective preventive and treatment strategies. Mitochondria are essential cellular organelles responsible for energy production through oxidative phosphorylation (OXPHOS). OXPHOS is a metabolic pathway that occurs in the inner mitochondrial membrane and involves a sequence of enzymatic reactions that generate adenosine triphosphate (ATP), the primary energy-supplying molecule for cells. Mitochondrial dysfunction, characterized by impaired OXPHOS, can lead to a range of cellular and physiological abnormalities. Mitochondrial oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and the ability of the cell's antioxidant defenses to neutralize them. Mitochondrial oxidative stress involves a cascade of interconnected mechanisms. Initially, electron leakage from the ETC complexes can engage with molecular oxygen, resulting in the formation of superoxide radicals. Subsequently, these superoxide radicals can undergo enzymatic and non-enzymatic reactions to form other ROS, such as hydrogen peroxide. This process is exacerbated by dysregulation of the ETC or impaired mitochondrial function, which amplifies ROS production. Factors like mitochondrial DNA (mtDNA) mutations, defects in ETC complexes, and loss of membrane potential contribute to this increased ROS generation. Additionally, mitochondria possess various antioxidant defenses to counteract ROS accumulation. Antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, along with non-enzymatic antioxidants like glutathione (GSH), play crucial roles in scavenging ROS and maintaining redox balance. However, when the levels of ROS surpass the capabilities of these defense mechanisms, mitochondrial proteins, lipids