Fig. 3

DENV-induced AMPK inactivation enhances HMGCR activity by activating SREBPs, leading to increased cholesterol accumulation in the ER. In contrast, transient AMPK activation coupled with mTORC1 inhibition is crucial for DENV-induced lipophagy, facilitating lipid droplet depletion and autophagy to support viral replication. Statins inhibit HMGCR, disrupting cholesterol biosynthesis and DENV replication while enhancing the innate immune response by suppressing isoprenoid synthesis. Similarly, metformin activates AMPK, reducing cholesterol and fatty acid synthesis via direct enzyme inactivation and SREBP regulation, while also inducing IFN-mediated responses to strengthen antiviral immunity. AMPK: AMP-Activated Protein Kinase; HMCGR: 3-Hydroxy-3-Methylglutaryl-CoA Reductase; mTORC1: Mechanistic Target of Rapamycin Complex 1; SREBP: Sterol Regulatory Element-Binding Protein; ACS: Acyl-CoA Synthetase; FAS: Fatty Acid Synthase; MVD: Mevalonate Diphosphate Decarboxylase; DHCR7: 7-Dehydrocholesterol Reductase. Reprinted with modifications by permission from ref [99]