Macrophage and inflammation in diabetes and metabolic dysfunction-associated steatotic liver disease: From mechanisms to therapeutic strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is featured by the accumulation of excessive fat in the liver. It is caused by many factors, such as overweight, obesity, diabetes, and high plasma levels of sugar, cholesterol, and triglycerides. MASLD is commonly associated with type 2 diabetes (T2D), which is characterized by a pathophysiological deficiency of insulin secretion due to impaired function of pancreatic β cells and insulin resistance. T2D has become a global pandemic that influences more than 21.7 million people worldwide. Pre-clinical and clinical studies have been performed to investigate molecular crosslinks between T2D and MASLD and their therapeutic strategies. Accumulating evidence has demonstrated that macrophages are cellular mediators that contribute to the progression of MASLD and T2D by impacting the resolution of inflammation. Different types of macrophages are involved in the pathogenesis of MASLD and T2D, including liver-resident macrophages or Kupffer cells, monocyte-derived macrophages, and adipose tissue macrophages. These macrophages secrete enzymes, chemokines, cytokines, as well as exosomes, to induce metabolic inflammation and insulin resistance, immune cell infiltration, and tissue injury. In this review, we provide a comprehensive summary of the molecular and cellular interactions between MASLD and T2D with a specific discussion of the critical roles of macrophages and inflammation. The underlying molecular mechanisms and the associated therapeutic targets and strategies are also reviewed.