AMER1 deficiency promotes the distant metastasis of colorectal cancer by inhibiting SLC7A11- and FTL-mediated ferroptosis

The crosstalk between ferroptosis and cancer metastasis remains unclear. Here, we identify AMER1 as a key regulator of ferroptosis. AMER1 loss causes resistance to ferroptosis in colorectal cancer (CRC) cells. Interestingly, AMER1-deficient CRC cells preferentially form distant metastases, while AMER1-naive CRC cells mainly invade lymph nodes. Moreover, the ferroptosis inhibitor liproxstatin-1 effectively promotes hematogenous transfer of AMER1-naive cells. Mechanistically, AMER1 binds to SLC7A11 and ferritin light chain (FTL) and recruits β-TrCP1/2, which degrade SLC7A11 and FTL by ubiquitination. Therefore, AMER1 deficiency increases cellular cystine levels but decreases the pool of labile free iron, thereby enhancing resistance to ferroptosis in CRC cells. Thus, AMER1 deficiency increases the survival of CRC cells in the blood under conditions of high oxidative stress and then promotes hematogenous metastasis of CRC. In conclusion, AMER1 mediates the crosstalk between ferroptosis and cancer metastasis, which provides a window of opportunity for treating metastatic colorectal cancer patients with AMER1 mutations. [Display omitted] •AMER1 has a high rate of truncating mutation in CRC with synchronous liver metastases•AMER1 functions as a common upstream regulator of system xc− and the labile iron pool•AMER1 regulates ubiquitination and degradation of SLC7A11 and FTL•AMER1 deficiency inhibits ferroptosis and facilitates CRC cell hematogenous metastasis Lei et al. identify AMER1 as a key regulator of ferroptosis in colorectal cancer. AMER1 acts as a common upstream regulator of system xc− and the labile iron pool by promoting ubiquitination and degradation of SLC7A11 and FTL, and its deficiency suppresses ferroptosis and facilitates CRC cell hematogenous metastasis.