Mesuaferroic acid H suppresses HepG2 cell proliferation by disrupting iron homeostasis via transferrin targeting

Mesua ferrea L., a medicinal plant widely utilized in traditional Chinese and South Asia medicine, demonstrates diverse pharmacological activities, with particularly notable anti-cancer properties. However, the specific bioactive constituents responsible for these effects and their underlying mechanisms remain unclear. This study aims to explore the cytotoxic potential of polycyclic polyprenylated acylphloroglucinols (PPAPs) (1-7) isolated from the petroleum ether extract of M. ferrea flowers in five cancer cell lines. Among them, mesuaferroic acid H (MAH) exhibits the most potent anti-proliferative activity with IC₅₀ of 4.18 ± 1.07 μM against HepG2 cells. Further investigations demonstrate that MAH significantly suppresses HepG2 cell proliferation, migtation and invasion through inducing apoptosis via the Caspase-3 signaling pathway, as evidenced by colony formation, wound healing and Transwell assays, and flow cytometry analysis. Importantly, activity-based protein profiling and click chemistry technologies identify transferrin (TF) as a key target of MAH, which directly binds to TF, to disrupt iron homeostasis in HepG2 cells. This was supported by quantitative real-time PCR, western blot, rescue experiments and molecular docking analysis. Moreover, the antitumor efficacy of MAH was confirmed in a xenograft mouse model. In conclusion, our study elucidates that MAH inhibits HepG2 cell proliferation by targeting transferrin, causing iron dysregulation and subsequent inhibition of HepG2 cell growth. These findings not only identify a potential molecular target for anti-cancer drug development but also provide a mechanistic basis for the anti-tumor activity of M. ferrea.