Fig. 1: Cys uptake can inhibit ferroptosis independently of GPX4.
From: Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals
a, Pathways by which cellular Cys2 uptake may contribute to ferroptosis resistance. On the one hand, Cys serves the biosynthesis of GSH, which is required by GPX4 to reduce oxidized lipids (upper branch). On the other hand, Cys is a source of S0 species, which may counteract lipid oxidation in a GPX4-independent manner (lower branch). b, S0 levels measured by SSP4 staining 4 hours after treatment of HeLa cells with either RSL3 (5 µM) or CHP (40 µM). n = 3. P = 0.0282 and 0.0500. c, S0 levels measured by SSP4 staining 48 hours after the addition of 4-hydroxytamoxifen (Tam, 0.75 µM) and liproxstatin-1 (Lipr, 1 µM) to Pfa1 cells. n = 3. P = 0.0070 and 0.0377. d, GSSH/GSSSH levels measured by LC–MS 24 hours after the addition of 4-hydroxytamoxifen (Tam, 0.75 µM) to Pfa1 cells. Left panel: n = 3 (mock), n = 5 (Tam), P = 0,0754; right panel: n = 4 (mock), n = 3 (Tam), P = 0.0015. e, Cys levels as measured by LC–MS in Pfa1 and xCT OE cells. n = 5. P = 0.00007. f, GSSH, GSSSH and GSH levels in Pfa1 and xCT OE cells as measured by LC–MS. Left panel: n = 3, P = 0.0251; middle panel: n = 3, P = 0.0504; right panel: n = 4, P = 0.0103. g, Cell viability after 72 hours of incubation with 4-hydroxytamoxifen (Tam, 0.5 µM), measured with an ATP assay (left panel) and a PrestoBlue (reduction capacity) assay (right panel) in Pfa1 and xCT OE cells. Left panel: n = 3, P = 0.00005; right panel: n = 3, P = 0.00004. h, Lipid aldehyde levels in Pfa1 and xCT OE cells, 48 hours after the addition of tamoxifen (Tam, 0.75 µM), as measured by CHH staining. n = 3. P = 0.0157, 0.0370, 0.0404 and 0.0397. Data are presented as mean values. For LC–MS data, error bars represent s.e.m. For the rest, error bars represent s.d. * P ≤ 0.05; ** P ≤ 0.01; *** P ≤ 0.001; and **** P ≤ 0.0001 based on a two-tailed unpaired t-test. OE, overexpressing.
