ANG secretion predisposes endothelial cells toward angiogenesis in FIN56-induced ferroptotic hepatocellular carcinoma via the BMP6/ID1 signaling pathway

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BACKGROUND: Hepatocellular carcinoma (HCC) poses significant challenges due to its high malignancy and limited treatment options. FIN56 has emerged as a potent inducer of ferroptosis, yet its precise mechanism of action in HCC remains elusive. METHODS: Ferroptosis induction by FIN56 in HCC cells was assessed by quantifying malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), reactive oxygen species (ROS), glutathione (GSH) and Liperfluo levels, as well as evaluating changes in mitochondrial morphology. Additionally, cell proliferation and migration assays were performed to assess the functional impact of FIN56 on HCC cells. Tube formation and sprouting assays were performed using human umbilical vein endothelial cells (HUVECs). Proteomics analysis and immunosorbent assay (ELISA) identified angiogenin (ANG) as a secreted protein in the supernatant of HCC cells. Furthermore, both xenograft and syngeneic tumor models were established to investigate the potential impact of FIN56-induced ferroptosis on the tumor microenvironment. RESULTS: RNA sequencing analysis of FIN56-treated HCC cells identified differentially expressed genes mainly associated with ferroptosis, cell proliferation, and migration. FIN56 effectively induced ferroptosis in HCC cells, while simultaneously inhibiting their proliferation and migration. RNA sequencing of HUVECs exposed to conditioned medium (CM) from FIN56-treated HCC cells (FIN56-CM) showed significant alterations in endothelial cell growth and gene expression. Further experiments revealed that FIN56-treated HCC cells secreted substantial levels of ANG after 12-18h, which activated the BMP6/ID1 signaling axis in endothelial cells, thereby enhancing their tube formation. Notably, the BMP signaling inhibitor LDN214117 partially suppressed ANG-mediated effects on endothelial cells. Finally, both ferroptosis and pro-angiogenic effects of FIN56 were confirmed in xenograft tumor model. CONCLUSION: FIN56 induces ferroptosis in HCC cells, leading to the secretion of ANG. The secreted ANG acts as a critical signaling molecule, activating the BMP6/ID1 pathway in HUVECs and contributing to tumor microenvironment regulation.

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