Targeting AKT to treat liver disease: Opportunities and challenges

AKT, a serine/threonine kinase, is essential for liver homeostasis and is critically involved in the pathogenesis of a wide spectrum of liver diseases. It regulates multiple downstream signaling pathways Through phosphorylation of downstream substrates, AKT modulates key cellular processes including lipid metabolism, apoptosis, oxidative stress, and inflammation. Persistent liver injury, induced by viral infections, alcohol consumption, or high-fat diets, often triggers maladaptive repair mechanisms that can progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma., Recent studies have highlighted the pivotal role of aberrant AKT activation in various hepatic pathological processes, such as metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease, NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI). This review systematically explores the molecular mechanisms of AKT signaling in liver disease progression, with a focus on the isoform-specific roles of the AKT isoforms (AKT1, AKT2, AKT3). Furthermore, we discuss emerging therapeutic strategies targeting AKT, including small molecule inhibitors and RNA-based modification technologies, alongside the landscape of ongoing clinical trials. Emphasis is placed on early-stage therapeutic interventions and drug resistance mechanisms as a critical direction for future translational research. Overall, this review provides a comprehensive theoretical framework for understanding the multifaceted regulatory functions of AKT in liver diseases and offers valuable insights for the development of precision-targeted therapies.