Hepatocellular carcinoma (HCC) represents a significant form of liver cancer, accounting for the fourth-highest number of cancer-related deaths on a global scale.Ferroptosis, a form of regulated cell death characterised by iron-dependent lipid peroxidation, has been increasingly implicated in HCC cancer progression and the role of Kinesin Family Member 20A (KIF20A), a member of the kinesin superfamily proteins that is vital during mitosis, might contribute to the resistance to ferroptosis of HCC.Here, we identify KIF20A as a novel biomarker of HCC and characterize the underlying mechanisms inducing ferroptosis.

The genes that were differentially expressed in HCC and associated with ferroptosis were selected through an analysis of the GEO database and the Ferrdb website. The mRNA and protein levels of KIF20A were examined in HCC cell lines using RT-qPCR and western blotting, respectively. Experiments were conducted on the proliferation of HCC cells, as well as on ferroptosis, using overexpression and knockdown of KIF20A. Assays such as malondialdehyde (MDA) detection and Ferrorange assays were employed. Furthermore, the mechanisms by which KIF20A regulates ferroptosis in HCC were investigated.

Among the top 18 differentially expressed genes, we discovered KIF20A most potently related to the overall survival rate. The expression of KIF20A was significantly compared between HCC tissues and adjacent non-cancerous tissues. Our findings revealed that the proliferation of KIF20A-knockdown cells was significantly inhibited in two cell lines, SNU449 and PLC. Furthermore, we observed an increase in the levels of malondialdehyde (MDA), Fe²⁺, and intracellular reactive oxygen species (ROS) in these cells. Conversely, overexpressing this gene yielded opposite results. Knocking down KIF20A activates the pathway of ferroptosis through the KEGG pathway, and HMOX1 was identified by RNA sequencing as a downstream target of KIF20A influencing ferroptosis. Furthermore, our findings indicate that KIF20A inhibits ferroptosis in HCC cells via the HMOX1/SLC7A11/GPX4 pathway.

Collectively, our results uncover a novel role of KIF20A in the survival of HCC cells, their specific metabolic pathways linked to ferroptotic cell death. Our results suggest that KIF20A promotes the proliferation of HCC cells and inhibits ferroptosis by regulating the HMOX1/SLC7A11/GPX4 axis.