Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines

Sorafenib, a protein kinase inhibitor approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma, has been repeatedly reported to induce Ferroptosis by possibly involving inhibition of the cystine/glutamate antiporter, known as system x_c^-. Using a combination of well-defined genetically engineered tumor cell lines and canonical small molecule Ferroptosis inhibitors, we now provide unequivocal evidence that sorafenib does not induce Ferroptosis in a series of tumor cell lines unlike the cognate system x_c^- inhibitors sulfasalazine and erastin. We further show that only a subset of tumor cells dies by Ferroptosis upon sulfasalazine and erastin treatment, implying that certain cell lines appear to be resistant to system x_c^- inhibition, while Others undergo ferroptosis-independent cell death. From these findings, we conclude that sorafenib does not qualify as a bona fide Ferroptosis inducer and that Ferroptosis induced by system x_c^- inhibitors can only be achieved in a fraction of tumor cell lines despite robust expression of SLC7A11, the substrate-specific subunit of system x_c^-.