Targeting cAMP signaling and phosphodiesterase 4 for liver disease treatment.

Liver disease is a significant health burden globally and accounts for 4% of total deaths annually. Alcoholic liver disease (ALD) and metabolism-associated fatty liver disease (MAFLD) are the leading causes of cirrhosis. Extensive studies have investigated the pathogenesis and molecular mechanisms underlying the diseases. However, there remains an urgent need for effective therapeutics. Cyclic adenosine monophosphate (cAMP) is the most studied intracellular second messenger, and its level is directly regulated by phosphodiesterase 4 (PDE4). PDE4 inhibitors are developed and marketed as a large category of drugs. Recent studies have revealed the significant role of cAMP in liver disease progression and evaluated the therapeutic efficacy of PDE4 inhibitors. PDE4 inhibitors exhibited efficacy in ameliorating ALD by reducing inflammation and mediating lipid metabolism. MAFLD, which shares similar disease features to ALD, was attenuated by PDE4 inhibitors due to improved homeostasis of fatty acid metabolism and insulin resistance. Fibrosis, which indicates the late stage of ALD and MAFLD progression, has been shown to improve with PDE4 inhibitors by inhibiting hepatic stellate cell (HSC) activation. However, the results from clinical trials evaluating PDE4 inhibitors for MAFLD management have been conflicting, highlighting the need for further validation and translation of preclinical findings to clinical settings.