Fig. 8: Proposed mechanisms of Tetrandrine action on the autophagic system, cholesterol metabolism, and IGF–Insulin signaling during SARS-CoV-2 infection.

This schematic representation summarizes the potential cellular targets and dose-dependent effects of Tetrandrine during the SARS-CoV-2 life-cycle in host cells. Tetrandrine appears to interfere with the IGF–Insulin signaling pathway, which has been reported to inhibit mTOR and, consequently, promote autophagy induction via the canonical autophagic pathway. In parallel, the compound influences cellular cholesterol homeostasis by blocking lysosomal cholesterol release via LIMP-2. Since SARS-CoV-2 requires cytosolic cholesterol for replication and assembly, this effect may explain the antiviral properties of Tetrandrine. In addition, we reported that at a lower concentration (5 µM), Tetrandrine primarily induces autophagy, as shown by increased formation of autophagic vacuoles, suggesting an enhancement of autophagic flux which could aid in degrading viral components. Conversely, at a higher concentration (10 µM), Tetrandrine seems to impair the late stages of autophagy, likely by disrupting autophagosome-lysosome fusion or lysosomal function, resulting in the accumulation of autophagosomes. These findings suggest a concentration-dependent mechanism in which Tetrandrine differentially modulates autophagy during SARS-CoV-2 infection. Moreover, the alteration of the IGF–like axis and cholesterol metabolism induced by Tetrandrine may collectively contribute to the inhibition of SARS-CoV-2 translation and replication, emphasizing its multifaceted antiviral potential. (Prepared by the author with Biorender.com, 2025).