Quercetin inhibits wild-type transthyretin fibril formation and attenuates associated cytotoxicity in vitro.

The misfolding and subsequent aggregation of transthyretin (TTR) into amyloid fibrils, which deposit in tissues such as the heart and peripheral nerves, underlies a series of progressive and fatal diseases. Consequently, molecules that inhibit protein misfolding represent a promising therapeutic strategy. Structural analysis of the TTR-quercetin complex indicates that quercetin stabilizes the TTR tetramer. In this study, Thioflavin T fluorescence assays, transmission electron microscopy, circular dichroism spectroscopy, and Fourier transform infrared spectroscopy demonstrated that quercetin significantly delays the aggregation rate of TTR. This leads to a decrease in β-sheet content and fibril formation. Furthermore, the inhibition of fibrillogenesis by quercetin significantly attenuated the cytotoxicity induced by TTR fibrils. These findings suggest that quercetin holds promise as a natural product for treating transthyretin amyloidosis. However, further in vivo studies and clinical trials are required to validate these findings and explore its translational potential.