KIF14–AKT axis regulates ferroptosis sensitivity in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited targeted treatment options. Ferroptosis has emerged as a potential therapeutic vulnerability in TNBC, but its upstream regulation remains incompletely defined. Here, we combined bioinformatics analysis with cell-based experiments to investigate the role of kinesin family member 14 (KIF14) in ferroptosis sensitivity. KIF14 was upregulated in TNBC datasets and associated with poor prognosis. In MDA-MB-468 cells, KIF14 knockdown reduced cell viability, increased malondialdehyde and intracellular Fe2+ levels, and induced mitochondrial changes consistent with ferroptosis. These effects were partially reversed by ferrostatin-1. Comparison with inhibitors of apoptosis, necroptosis, and pyroptosis showed that only ferrostatin-1 produced a clear rescue effect, supporting a predominantly ferroptosis-associated phenotype. Mechanistically, KIF14 depletion reduced phosphorylation of AKT serine/threonine kinase (AKT) and altered ferroptosis-related proteins, including decreased glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) and increased acyl-CoA synthetase long-chain family member 4 (ACSL4). The AKT activator SC79 partially reversed these biochemical and phenotypic changes. Reciprocal co-immunoprecipitation further supported an association between endogenous KIF14 and AKT. In addition, KIF14 knockdown had minimal effects on the viability of normal MCF-10A cells. Together, these findings support a functional link between KIF14, AKT signaling, and ferroptosis sensitivity in TNBC.