Fig. 6: Simvastatin overcomes ferroptosis resistance in Immune-refractory tumors via Inhibition of the HMGCR–CoQ10 Axis.

Cell death percentage of B16 P0 and P3 cells (a) or A375 P0 and P3 cells (b) treated with indicated concentrations of RSL3 with or without simvastatin (Sim, 1 μM) for 24 h. The percentage of cell death was determined by trypan blue exclusion assay. The percentage of 7AAD⁺ cells or relative lipid ROS in B16 P3 cells (c) and in A375 P3 cells (d) treated for 48 h with RSL3 and Sim with or without Lip-1 (1 μM) for an additional 20 h. e The mevalonate pathway and its metabolic branches in mammalian cells, highlighting key enzymatic steps catalyzed by HMGCR, COQ2, FDFT1, and SQLE, along with their respective inhibitors. f The levels of CoQ10 and cholesterol in A375 P0 and P3 cells. The percentage of 7AAD⁺ tumor cells and lipid ROS levels were measured in A375 P3 cells treated with RSL3 (200 nM) alone or in combination with ZA (20 μM) (g) or 4-NB (1 mM) (h), with or without Lip-1 (1 μM). i The levels of CoQ10 in A375 cells treated with or without simvastatin. j The percentage of 7AAD⁺ tumor cells and relative lipid ROS levels were assessed in A375 P3 cells treated with RSL3 (200 nM) alone or in combination with Sim (1 μM), with or without CoQ10 (200 μM) supplementation. All in vitro experiments were performed in triplicate. The error bars represent mean ± SD. All p value are presented exactly in figure. The p values by two-way ANOVA (a–d, g, h, j), and unpaired, two-tailed Student’s t test (f, i) are indicated. Source data are provided as a Source data file.