Pioglitazone Reduces Hepatic Alpha-1 Antitrypsin Accumulation Through Autophagy and AMPK Activation in Alpha-1 Antitrypsin Deficient Mice

Alpha-1 antitrypsin deficiency (AATD) mediated liver disease lacks therapies that reduce hepatic ZAAT accumulation and liver manifestations. We demonstrate that pioglitazone activates AMPK and induces autophagy, leading to decreased ZAAT and improved proteostasis in Pi*Z mouse livers and human hepatocyte models. As an FDA-approved drug with metabolic benefits, pioglitazone holds promise for repurposing in AATD-related liver disease. These findings offer a mechanistic rationale for targeting autophagy to alleviate hepatic injury in protein misfolding disorders.