Targeting Integrin αvβ3 with ProAgio: A Novel Strategy for the Treatment of MASH and AH

Metabolic dysfunction–associated steatohepatitis (MASH) and alcohol-associated steatohepatitis (AH) are burgeoning chronic liver conditions that affect significant portions of the global population. Dysregulated lipid metabolism and alcohol-induced toxicity drive the disease progression primarily through activation of hepatic stellate cells (HSCs) and capillarization of liver sinusoidal endothelial cells (LSECs). This process leads to collagen deposition and sinusoidal remodeling which ultimately alters sinusoidal architecture resulting in hepatic inflammation, portal hypertension, liver failure and various other complications. Numerous efforts have been made to develop effective treatments for MASH and AH though success remains limited, and outcomes often fail to achieve significant reduction in fibrosis. Here we introduce an innovative therapeutic strategy for the treatment of MASH and AH utilizing ProAgio, a specifically engineered protein to induce apoptosis in integrin αvβ3-positive cells. Integrin αvβ3 is notably overexpressed in activated hepatic stellate cells angiogenic endothelium and capillarized liver sinusoidal endothelial cells within the diseased liver. ProAgio selectively induces apoptosis in these key cell populations thereby reducing collagen deposition reversing sinusoidal remodeling and limiting immune cell infiltration. Restoration of normal sinusoidal architecture further decreases leukocyte adhesion molecule expression on LSECs which in turn reduces leukocyte infiltration and activation in the liver. Our findings underscore a promising and targeted therapeutic approach for effective management of MASH and AH.