Metabolic dysfunction-associated steatohepatitis (MASH) is the most common cause of liver disease globally, with only one approved therapeutic. Interleukin-22 (IL-22) has shown potential in preclinical models of diabetes by reducing β-cell stress, inflammation, and insulin resistance. However, long-acting IL-22 forms can cause unwanted effects like skin and intestinal hyperproliferation. To address this, researchers developed short-acting IL-22-bispecific biologics targeting the liver and pancreas. These biologics showed greater efficacy than native IL-22 in multiple MASH models, improving glycemic control, reducing steatosis, inflammation, and fibrosis without off-target effects. In preclinical studies, IL-22-bispecific biologics reduced hepatic lipid accumulation and improved glucose tolerance. They also reduced ER stress and inflammation in the liver and pancreas, with minimal effects on the skin and intestine. The biologics were more stable and effective than native IL-22, with a 10-fold lower dose achieving similar results. Targeting the liver and pancreas reduced fibrosis and improved metabolic parameters, including insulin production and glucose handling. The study demonstrated that IL-22-ScFv, a bispecific fusion targeting liver and pancreas, significantly reduced fibrosis and improved metabolic outcomes in multiple MASH models. It also reduced ER stress and inflammation in the liver and pancreas, with minimal effects on the skin and intestine. The biologics showed enhanced targeting to the liver and pancreas compared to native IL-22, with no off-target effects. The findings suggest that targeted IL-22 therapy could be a promising treatment for MASH, offering improved efficacy and reduced side effects compared to traditional therapies. The study highlights the potential of IL-22-bispecific biologics as a novel therapeutic approach for MASH, targeting multiple pathways involved in the disease.Metabolic dysfunction-associated steatohepatitis (MASH) is the most common cause of liver disease globally, with only one approved therapeutic. Interleukin-22 (IL-22) has shown potential in preclinical models of diabetes by reducing β-cell stress, inflammation, and insulin resistance. However, long-acting IL-22 forms can cause unwanted effects like skin and intestinal hyperproliferation. To address this, researchers developed short-acting IL-22-bispecific biologics targeting the liver and pancreas. These biologics showed greater efficacy than native IL-22 in multiple MASH models, improving glycemic control, reducing steatosis, inflammation, and fibrosis without off-target effects. In preclinical studies, IL-22-bispecific biologics reduced hepatic lipid accumulation and improved glucose tolerance. They also reduced ER stress and inflammation in the liver and pancreas, with minimal effects on the skin and intestine. The biologics were more stable and effective than native IL-22, with a 10-fold lower dose achieving similar results. Targeting the liver and pancreas reduced fibrosis and improved metabolic parameters, including insulin production and glucose handling. The study demonstrated that IL-22-ScFv, a bispecific fusion targeting liver and pancreas, significantly reduced fibrosis and improved metabolic outcomes in multiple MASH models. It also reduced ER stress and inflammation in the liver and pancreas, with minimal effects on the skin and intestine. The biologics showed enhanced targeting to the liver and pancreas compared to native IL-22, with no off-target effects. The findings suggest that targeted IL-22 therapy could be a promising treatment for MASH, offering improved efficacy and reduced side effects compared to traditional therapies. The study highlights the potential of IL-22-bispecific biologics as a novel therapeutic approach for MASH, targeting multiple pathways involved in the disease.