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).

Metabolic dysfunction-associated steatohepatitis (MASH), an advanced manifestation of metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 30% of adults worldwide. Fatty acids, as important nutrients, are absorbed and utilized in a complex mixture daily. Medium-chain fatty acids are recommended for patients with lipid metabolism disorders due to their favorable metabolic properties and linoleic acid (LA-l, an essential fatty acid) is commonly consumed, but their combined effects in MASH remain unclear. Therefore, in this study, we employed multi-level models and lipidomics to investigate the combined effects of lauric acid (LA-m) and LA-l under normal and MASH conditions. The results revealed that co-intake of LA-m and LA-l exacerbated hepatotoxicity specifically in MASH, but not in healthy conditions, indicating metabolic status may determine susceptibility. Mechanistically, this combination increased membrane sphingolipid accumulation under the MASH diet, inducing endoplasmic reticulum stress, and ultimately triggering hepatotoxicity. Moreover, the combination increased ACSL4 expression to generate AA/AdA-PE, suggesting that LA-m may make hepatocytes more sensitive to ferroptosis by promoting the esterification of LA-l. Collectively, these findings provide caution in the concomitant use of LA-m and LA-l in MASH patients.