Investigating the mechanism of ferroptosis induction by sappanone A in hepatocellular carcinoma: NRF2/xCT/GPX4 axis

Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy with significant global impact, necessitating the development of novel therapeutic strategies and drugs. Ferroptosis, a newly identified form of irondependent programmed cell death, has emerged as a promising strategy to combat HCC. Sappanone A, an isoflavone compound derived from the heartwood of Biancaea sappan (L.) Tod., is known for its anti-inflammatory and antioxidant properties. However, its anti-HCC effects and underlying mechanisms remain unclear. This study is the first time to demonstrate the anti-tumor effect of Sappanone A on HCC both in vitro and in vivo, through the assessment of cell viability and apoptosis following Sappanone A treatment. Flow cytometry and confocal microscopy revealed that Sappanone A induced ferroptosis in HCC cells by increasing Fe2+ accumulation, reactive oxygen (ROS) level, and lipid peroxidation, specifically targeting inosine monophosphate dehydrogenase-2 (IMPDH2). Additionally, Western blot analysis suggested that the anti-HCC effects of Sappanone A were mediated through the regulation of the NRF2/xCT/GPX4 axis, highlighting its potential to enhance ferroptosis in HCC cells and underscoring the critical role of IMPDH2 in HCC treatment.