Aurantio-obtusin regulates lipogenesis and ferroptosis of liver cancer cells through inhibiting SCD1 and sensitizing RSL3

Ferroptosis, characterized by iron-mediated non-apoptotic cell death and alterations in lipid redox metabolism, has emerged as a critical process implicated in various cellular functions, including cancer. Aurantio-obtusin (AO), a bioactive compound derived from Cassiae semen (the dried mature seeds of Cassie obtusifolia L. or Cassia toral L.), has anti-hyperlipidemic and antioxidant properties; however, to the best of our knowledge, the effect of AO on liver cancer cells remains unclear. The Cell Counting Kit-8, EdU staining and migration assays were employed to assess the anti-liver cancer activity of AO. Intracellular levels of glutathione peroxidase 4 protein and lipid peroxidation were measured as indicators of ferroptotic status. Immunohistochemical analyses, bioinformatics analyses and western blotting were conducted to evaluate the potential of stearoyl-CoA desaturase 1 (SCD1) in combination with ferroptosis inducers for the personalized treatment of liver cancer. The present study revealed that AO significantly inhibited the proliferation of liver cancer cells in vitro and in vivo. Mechanistically, AO inhibited AKT/mammalian target of rapamycin (mTOR) signaling, suppressed sterol regulatory element-binding protein 1 (SREBP1) expression, and downregulated fatty acid synthase expression, thereby inhibiting de novo fatty acid synthesis. Further investigations demonstrated that AO suppressed glutathione peroxidase 4 protein expression through the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway, induced ferroptosis in liver cancer cells, and simultaneously inhibited lipogenesis by suppressing SCD1 expression through the AKT/mTOR/SREBP1 pathway. Consequently, this increased the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. Additionally, the enhanced effects of AO and RSL3, which resulted in significant tumor suppression, were confirmed in a xenograft mouse model. In conclusion, the present study demonstrated that AO induced ferroptosis, downregulated the expression of SCD1 and enhanced the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. The synergistic use of AO and a ferroptosis inducer may have promising therapeutic effects in liver cancer cells.