Fig. 4. FSP1 mediates ferroptosis resistance in lung cancer.
a,b, High expression of FSP1 is correlated with resistance to GPX4 inhibitors in non-hematopoietic cancer cells. Plotted data was mined from the CTRP database that contains correlation coefficients between gene expression and drug sensitivity for 907 cancer cell lines treated with 545 compounds. (a) shows the correlation between FSP1 expression and resistance to individual compounds and (b) shows the correlation between expression levels of individual genes and resistance to RSL3. Plotted values are z-scored Pearson’s correlation coefficients. c, Dose response of RSL3-induced cell death of the indicated cell lines. d, Dose response of RSL3-induced cell death of control and FSP1KO H460 cells. e, Dose response of RSL3-induced cell death of FSP1-GFP H1703 cells. f, Time lapse analysis of cell death of GPX4KO and GPX4KO/FSP1KO H460 cells in the presence and absence of 1 μM Fer1. g, GPX4KO/FSP1KO H460 tumor xenografts cells were initiated in immune-deficient SCID mice (n = 16). Following 5 days of daily Fer1 injections (2 mg/kg) to allow the cell lines to develop tumors, one set of mice (n = 8) continued to receive daily Fer1 injections and a second set (n = 8) received vehicle injections for the remaining 17 days. The distribution of fold changes in sizes of individual tumors during the treatment is shown. GPX4KO/FSP1KO (−) Fer1, n = 7); GPX4KO/FSP1KO (+) Fer1, n = 8. Box plots indicate median, 25th and 75th percentiles, minima and maxima of the distributions. Day 15, *P = 0.0397; Day 17, *P = 0.0187; Day 18, **P = 0.0025; Day 21, *P = 0.0327 by two-tailed t-test. h, Model illustrating the mechanism by which FSP1 suppresses ferroptosis. For figures c-e, shading indicates 95% confidence intervals for the fitted curves and each data point is the average of 3 technical replicates. Figures c-f are representative of two biological replicates.