Circular RNA FUT8 Suppresses Ferroptosis to Promote Hepatocellular Carcinoma Progression via the miR-125a-3p/SUSD2 Axis

Background Hepatocellular carcinoma (HCC) is a major global cause of cancer death. Ferroptosis, an iron-dependent cell death driven by lipid ROS and peroxidation, suppresses tumor growth. CircRNAs act as ceRNAs to sponge miRNAs and modulate tumor progression. CircFUT8 (hsa_circ_0003028) is markedly upregulated in HCC based on GSE97332 dataset, yet its role in HCC remains poorly defined. This study explored the oncogenic function and underlying mechanism of circFUT8 in HCC. Methods We analyzed circFUT8 expression in HCC tissues and cell lines via public databases and qRT-PCR validation. CircFUT8’s circular characteristics were verified by circular sequencing, RNase R resistance assay, FISH and Northern blot. Functional assays were performed to explore its effects on HCC proliferation, metastasis and ferroptosis inhibition in vitro. Bioinformatics prediction, RIP, dual-luciferase reporter assay and Western blot were further used to clarify the downstream molecular mechanism of circFUT8. Results We found that hsa_circ_0003028 (circFUT8) was significantly upregulated in HCC tissues and cell lines, with predominant cytoplasmic localization. In vitro functional assays revealed that circFUT8 knockdown markedly suppressed the proliferation and migration of HCC cells, while sensitizing cells to ferroptosis; conversely, circFUT8 overexpression yielded the opposite phenotypic effects. Mechanistically, circFUT8 functions as a competitive endogenous RNA (ceRNA) to sponge miR-125a-3p, thereby elevating the expression of its downstream target gene SUSD2. The circFUT8/miR-125a-3p/SUSD2 regulatory axis facilitates HCC malignant progression and attenuates cellular ferroptosis sensitivity. Conclusion This study is the first to reveal that circFUT8 attenuates ferroptosis sensitivity in HCC via the miR-125a-3p/SUSD2 axis. Moreover, our findings firstly identify the regulatory role of SUSD2 in tumor ferroptosis.