Ma Jingyi, Staler Dalton W, Mahato Ram I
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
Med Chem Res. 2024 Aug;33(8):1339-1353. doi: 10.1007/s00044-024-03267-3. Epub 2024 Jun 26.
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.
肝脏疾病是全球重大的健康负担，每年占总死亡人数的4%。酒精性肝病（ALD）和代谢相关脂肪性肝病（MAFLD）是肝硬化的主要原因。广泛的研究已经调查了这些疾病的发病机制和分子机制。然而，仍然迫切需要有效的治疗方法。环磷酸腺苷（cAMP）是研究最多的细胞内第二信使，其水平直接受磷酸二酯酶4（PDE4）调节。PDE4抑制剂作为一大类药物被开发并上市。最近的研究揭示了cAMP在肝脏疾病进展中的重要作用，并评估了PDE4抑制剂的治疗效果。PDE4抑制剂通过减轻炎症和调节脂质代谢，在改善ALD方面表现出疗效。MAFLD与ALD具有相似的疾病特征，由于脂肪酸代谢和胰岛素抵抗的内稳态得到改善，PDE4抑制剂使其病情得到缓解。纤维化是ALD和MAFLD进展的晚期阶段，已表明PDE4抑制剂通过抑制肝星状细胞（HSC）激活可改善纤维化。然而，评估PDE4抑制剂用于MAFLD治疗的临床试验结果相互矛盾，这突出表明需要进一步验证并将临床前研究结果转化到临床环境中。
