Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. The mechanisms orchestrating such an infection course remain to be elucidated. In the context of viral infection, adenosine monophosphate activated protein kinase (AMPK) appears to perform virus-associated metabolic remodeling activities that play an adaptive role, either in promoting or inhibiting viral replication. However, the role of AMPK in HEV replication is still unclear.
A recent study led by Dr. Yijin Wang from Southern University of Science and Technology, Dr. Jian Wu from Affiliated Suzhou Hospital of Nanjing Medical University and Dr. Qiuwei Pan from Erasmus University Medical Center, demonstrated the dual therapeutic potential of hepatitis E through anti-inflammatory and antiviral activity through the agitation of AMPK.
In this study, they found that HEV infection, either acutely or chronically, could potently activate the key metabolic sensor AMPK, which in turn suppressed HEV replication. Mechanistically, HEV injuries mitochondria, interfering with energy generation. AMPK, which monitors the cellular energy status, is activated by increased ratios of AMP:ATP and ADP: ATP during HEV infection. On the one hand, AMPK activation directly reinforces the HEV-induced innate immune response by combining with TBK1; on the other hand, it contributes to HEV-suppressed autophagosomes, resulting in the suppression of HEV replication. Moreover, activated AMPK attenuated the inflammatory response in HEV-infected macrophages.
In conclusion, HEV infection activated AMPK, which regulates the innate antiviral response and autophagy to inhibit viral replication collectively. Importantly, pharmacological activation of AMPK simultaneously inhibits HEV infection and the inflammatory response. In addition, this therapeutic effect was further augmented when AICAR was combined with another anti-inflammatory regimen, dexamethasone. Future studies should focus on evaluating the antiviral effects of AMPK against HEV in vivo models. These results offer an attractive, promising therapeutic option for severe hepatitis E, warranting further research in animal models and patients.
Read the full research article (Cell Mol Life Sci. 2025 Mar 13;82(1):111.): DOI: 1007/s00018-025-05634-8
