Naringenin enhances the efficacy of ferroptosis inducers by attenuating aerobic glycolysis by activating the AMPK-PGC1α signalling axis in liver cancer
Yong-Zhuo Li,
Jing Deng,
Xiao-Dong Zhang,
Dong-Yang Li,
Li-Xi Su,
Shan Li,
Jian-Min Pan,
Lan Lu,
Jia-Qi Ya,
Nuo Yang,
Jing Zhou,
Li-Hui Yang
Affiliations
Yong-Zhuo Li
Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi, China
Jing Deng
Academic Affairs Office, School of Nursing, Guangxi Medical University, Nanning, Guangxi, China
Xiao-Dong Zhang
Department of Gastrointestinal Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, Guangxi, China
Dong-Yang Li
Academic Affairs Office, School of Nursing, Guangxi Medical University, Nanning, Guangxi, China
Li-Xi Su
Academic Affairs Office, School of Nursing, Guangxi Medical University, Nanning, Guangxi, China
Shan Li
Academic Affairs Office, School of Nursing, Guangxi Medical University, Nanning, Guangxi, China
Jian-Min Pan
Department of Gastrointestinal Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, Guangxi, China
Lan Lu
Academic Affairs Office, School of Nursing, Guangxi Medical University, Nanning, Guangxi, China
Jia-Qi Ya
Academic Affairs Office, School of Nursing, Guangxi Medical University, Nanning, Guangxi, China
Nuo Yang
Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, Guangxi, China; Corresponding author.
Jing Zhou
Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi, China; Corresponding author.
Li-Hui Yang
Academic Affairs Office, School of Nursing, Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Biological Molecular Medicine Research(Guangxi Medical University), Guangxi Medical University, Nanning, Guangxi, China; Corresponding authors. Academic Affairs Office, School of Nursing, Guangxi Medical University, Nanning, Guangxi, China.
Liver cancer is a heterogeneous disease characterized by poor responses to standard therapies and therefore unfavourable clinical outcomes. Understanding the characteristics of liver cancer and developing novel therapeutic strategies are imperative. Ferroptosis, a type of programmed cell death induced by lipid peroxidation, has emerged as a potential target for treatment. Naringenin, a natural compound that modulates lipid metabolism by targeting AMPK, shows promise in enhancing the efficacy of ferroptosis inducers. In this study, we utilized liver cancer cell lines and xenograft mice to explore the synergistic effects of naringenin in combination with ferroptosis inducers, examining both phenotypic outcomes and molecular mechanisms. Our study results indicate that the use of naringenin at non-toxic doses to hepatocytes can significantly enhance the anticancer effects of ferroptosis inducers (erastin, RSL3, and sorafenib). The combination index method confirmed a synergistic effect between naringenin and ferroptosis inducers. In comparison to naringenin or ferroptosis inducers alone, the combined therapy caused more robust lipid peroxidation and hence more severe ferroptotic damage to cancer cells. The inhibition of aerobic glycolysis mediated by the AMPK-PGC1α signalling axis is the key to naringenin's effect on reducing ferroptosis resistance in liver cancer, and the synergistic cytotoxic effect of naringenin and ferroptosis inducers on cancer cells was reversed after pretreatment with an AMPK inhibitor or a PGC1α inhibitor. Taken together, these findings suggest that naringenin could boost cancer cell sensitivity to ferroptosis inducers, which has potential clinical translational value.
