For example, although there have been numerous studies reporting various beneficial metabolic effects of pharmaceutical drugs or dietary supplements that aim to mimic CR effects by broadly activating cAMP-dependent signaling pathways, such as resveratrol derivatives, adenylate cyclase agonists, and PDE4 inhibitors, their therapeutic efficacy on NAFLD has not been very consistent, and often even contradictory8, 14, 15, 16. Here, PDE4A is linked to metabolic dysfunction-associated steatotic liver disease.