Tetrandrine-Driven Autophagy Suppresses SARS-CoV-2 Replication by Modulating Cholesterol and IGF Signaling Pathways

SARS-CoV-2 exploits multiple host cellular processes, including autophagy—a critical intracellular degradation pathway—to facilitate viral replication and evade immune detection. Tetrandrine, a natural bis-benzylisoquinoline alkaloid derived from Stephania tetrandra, has been reported to modulate autophagy and exhibits potential antiviral properties. In this study, we investigated the effects of Tetrandrine on SARS-CoV-2 infection in human lung epithelial cells (Calu-3), with a particular focus on autophagy-related mechanisms. Our results demonstrate that Tetrandrine modulates autophagic activity in a dose-dependent manner and significantly reduces SARS-CoV-2 replication, particularly when administered prior to infection. Notably, its antiviral effect is retained in autophagy-deficient cells, indicating the involvement of autophagy-independent mechanisms. Proteomic analysis of Calu-3 cells infected with the Omicron BA.5 variant revealed that Tetrandrine regulates several host pathways implicated in viral replication, including autophagy, cholesterol metabolism, and insulin-like growth factor signaling. These findings suggest that Tetrandrine exerts multifaceted antiviral effects by targeting both autophagy-dependent and -independent cellular pathways. Collectively, our data supports the potential of Tetrandrine as a therapeutic candidate against COVID-19 and warns further evaluation in preclinical and clinical models. Data are available via ProteomeXchange with identifier PXD064448.