Monotropein Induced Ferroptosis to Alleviate the Progression of Hepatocellular Carcinoma via Regulating Nrf2/HO‐1/GPX4 Axis

ABSTRACT Hepatocellular carcinoma (HCC) exhibits a high global morbidity rate and ranks as the fourth leading cause of cancer‐related mortality worldwide. In response to the urgent need for effective HCC treatments, naturally occurring, botanical‐driven compounds have gained increasing attention. Notably, the anti‐tumor properties of some compounds might be linked to the induction of ferroptosis. The present study aimed to evaluate the capacity of Monotropein (Mon) to induce ferroptosis in HCC and elucidate its underlying mechanisms. First, Mon was found to play an anti‐tumor role in HCC cells by inhibiting cell proliferation and invasion, elevated the expression of E‐cadherin, and decreased N‐cadherin and Vimentin expression. Furthermore, Mon activated ferroptosis in HCC cells, characterized by elevated levels of Fe 2+ , reactive oxygen species (ROS), and malondialdehyde (MDA), alongside a reduction in glutathione (GSH) content and downregulation of nuclear factor E2‐related factor 2 (Nrf2), heme oxygenase‐1 (HO‐1), and glutathione peroxidase 4 (Gpx‐4). These in vitro findings were confirmed by in vivo tumorigenicity experiments. With regard to the mechanism, the suppression of Nrf2 signaling played a significant role in facilitating ferroptosis induced by Mon, ultimately slowing down the progression of HCC cells. In conclusion, this study revealed that Mon suppressed the progression of HCC both in vitro and in vivo, which was closely associated with ferroptosis induction via inhibiting Nrf2 signaling. These results suggest that Mon represents a promising alternative for HCC treatment.