Oblique-incidence Reflectivity Difference Technology Identifies the Antiviral Drug Ribavirin as an Inhibitor of Lung Tumor Progression by Targeting AMPK Signaling

Lung cancer takes the lead in terms of global cancer incidence and mortality rates. 5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) serves as a universally conserved energy sensor throughout evolution checkpoint that orchestrates energy balance and metabolic homeostasis. However, AMPK activation has a complex, dual function in both the onset and advancement of lung cancer. Despite its protumorigenic effects, targeting AMPK with inhibitors to suppress cancer progression remains a critical area of research. An innovative high-content screening platform integrating small-molecule microarrays (SMMs) with oblique-incidence reflectivity difference (OI-RD) optical detection was established for AMPK inhibitor discovery. Alterations in the interfacial refractive index revealed that Ribavirin, an antiviral drug, has a high affinity for AMPK. Ribavirin binds directly to AMPK, suppressing its activation in mouse and human cells. By inhibiting AMPK phosphorylation, Ribavirin affects the downstream phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), thereby regulating tumor cell proliferation and apoptosis. These results identify Ribavirin as a new AMPK inhibitor with potential utility in lung cancer therapy.