HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma
Jingsheng Yuan,
Tao Lv,
Jian Yang,
Zhenru Wu,
Lvnan Yan,
Jiayin Yang,
Yujun Shi
Affiliations
Jingsheng Yuan
Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China
Tao Lv
Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China
Jian Yang
Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China
Zhenru Wu
Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu, 610041, China
Lvnan Yan
Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China
Jiayin Yang
Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China; Corresponding author. Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
Yujun Shi
Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu, 610041, China; Corresponding author. Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China.
Recent studies have suggested that exploring the potential mechanisms regulating ferroptosis vulnerability may contribute to improving the systemic therapeutic efficacy in HCC. High-density lipoprotein-binding protein (HDLBP), the largest RNA-binding protein, is an important transporter that protects cells from overaccumulation of cholesterol, but few studies have elucidated the role of HDLBP in the regulation of ferroptosis vulnerability in HCC. Our study suggests that HDLBP was markedly elevated in HCC compared with noncancerous liver tissues and that this elevation inhibited the ferroptosis vulnerability of HCC. Further experiments revealed that HDLBP bound to and stabilized the long noncoding RNA lncFAL (ferroptosis-associated lncRNA), which is derived from the plexin B2 gene. Moreover, our study suggests that the splicing of lncFAL was increased by YTH N6-methyladenosine (m6A) RNA-binding protein 2 (YTHDF2) in a m6A-dependent manner. Although HDLBP or lncFAL could not regulate the GPX4 antioxidant signalling pathway, lncFAL reduced ferroptosis vulnerability by directly binding to ferroptosis suppressor protein 1 (FSP1) and competitively abolishing Trim69-dependent FSP1 polyubiquitination degradation. More importantly, FSP1 inhibition promoted the antitumour activity of ferroptosis inducers both in vitro and in vivo. Collectively, our results provide a clinically promising demonstration that HDLBP stabilizes lncFAL, which mediates a FSP1-dependent anti-ferroptosis mechanism in HCC. These results support the enormous potential of disrupting FSP1 as a promising therapeutic approach for HCC patients with high HDLBP or lncFAL expression.
