This study reports that high overexpression of the cystine transporter SLC7A11 increases cancer cell death under high H2O2 treatment, contrary to its protective role in moderate oxidative stress. This is due to excessive cystine uptake leading to intracellular disulfide buildup, NADPH depletion, and disulfidptosis, revealing a context-dependent role for SLC7A11 in cancer biology.

K.O. and L.K. are former full-time employees of Kadmon Corporation. M.V.P. is a full-time employee of Kadmon Corporation, a Sanofi Company.

This study provides strong evidence for a novel and surprising finding that high expression of SLC7A11, while protective against moderate oxidative stress, can become detrimental under high oxidative stress conditions. The study uses a variety of experimental approaches and provides mechanistic insights into the observed phenomenon. However, the reliance on in vitro and xenograft models, as well as the focus on H2O2-induced oxidative stress, are limitations that need to be acknowledged.