Ursolic acid sensitizes hepatoma cells to sulfasalazine-induced ferroptosis via AMPK/BECN1/SLC7A11-mediated redox disruption in vitro and in vivo

Targeting ferroptosis has emerged as a promising anti-cancer strategy. A Food and Drug Administration (FDA)-approved drug, sulfasalazine (SAS), also a ferroptosis inducer, is being explored as a potential treatment drug for cancer. However, long-term high-dose SAS treatment may induce several adverse effects in the liver. Our current study found that ursolic acid (UA), derived from traditional medicinal plants, fruits, and vegetables, enhanced the anti-tumor effects of low-dose SAS both in vitro (SMMC-7721 liver cells) and in vivo (a mouse tumor xenograft model). Treatment with a combination of UA and SAS reduced the glutathione (GSH), glutathione peroxidase 4 (GPX4), and promoted a substantial accumulation of lipid reactive oxygen species (ROS), leading to oxidative stress and ferroptosis. Mechanistically, the UA/SAS treatment significantly reduced the system xc⁻ activity and cystine uptake, attributed to the AMPK activation-induced formation of the SLC7A11-BECN1 complex. Moreover, the induction of NCOA4-mediated ferritinophagy also played a role in this process. Besides, UA sensitized hepatoma cells to erastin as well, another SLC7A11-targeting ferroptosis inducer, implying a potential use of UA as a SLC7A11-targeting enhancer to combat hepatocellular carcinoma (HCC).