NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis

During metastasis, cancer cells face significant survival pressures, including treatment-induced ferroptosis. Adaptation to ferroptosis stress orchestrates the metastasis of colorectal cancer (CRC) cells. However, the reciprocal regulatory mechanisms of ferroptosis and metastasis remain unknown. Here, through a CRISPR–Cas9 screen, we discovered that N-acetylneuraminate synthase (NANS) is a positive regulator of ferroptosis in CRC, regardless of its metabolic function. Moreover, NANS expression is downregulated and is clinically associated with poor prognosis in CRC patients. In a ferroptotic stress environment, NANS is phosphorylated by cyclin-dependent kinase 1 (CDK1) at serine 275 (S275), and phosphorylated NANS (NANS pS275) dissociates from TAK1 and is subsequently ubiquitinated by the E3 ligase ubiquitin-conjugating enzyme E2 N (UBE2N) at lysine 246 (K246) for degradation, which further activates TAK1 and nuclear factor κB (NF-κB) signaling and the expression of the ferroptosis negative regulatory factor FTH1, resulting in ferroptosis resistance and finally promoting metastasis. Furthermore, the NANS pS275 intensity is correlated with the degree of malignancy and the prognosis of CRC patients. Our study revealed that NANS inhibits CRC metastasis by promoting ferroptosis and that the CDK1-mediated phosphorylation of NANS at S275 may guide the utilization of chemical compounds to promote ferroptosis and thus block CRC metastasis.