Repurposing statins activates compensatory glutathione metabolism as synergistic vulnerability in colorectal cancer

Metabolic adaptations upon intrinsic and environmental stressors enable cancer cells to resist treatment and sustain proliferation. Understanding of adaptive rewiring and compensatory mechanisms is a pivotal strategy to develop effective treatment options. Statins are receiving increasing attention in the prevention of colorectal cancer (CRC), but the biological mechanism is elusive. Here, we demonstrate that six statins show effective tumor repression capacity in a dose-dependent manner. We next observe that administration of statin alone is not sufficient to induce programmed cell death because inhibitors of ferroptosis, apoptosis, necroptosis, and autophagy fail to rescue the cell viability. To further understand the therapeutic vulnerability, untargeted metabolic analysis is employed to detect the reprogramming metabolites. Pathway analysis shows glutathione metabolism is significantly perturbed. Meanwhile, dramatic increases of cysteine and gamma-glutamylcysteine are widely observed while the reduced glutathione (GSH) and oxidized glutathione (GSSG) levels are decreased, linked to redox imbalance and ferroptosis. Western blotting shows statins have similar effects as RSL3 on increasing the expression of glutamate-cysteine ligase catalytic subunit (GCLC), which catalyzes the rate-limiting step of GSH synthesis, and its inhibition is associated with ferroptosis induction. In contrast, CRC cells show increasing reliance on glutathione peroxidase 4 (GPX4) upon statins treatment when compare to RSL3. Collectively, compensatory upregulation of GCLC indicates combinations of statins and GCLC inhibitors may enhance antiproliferative efficacy of targeting GSH metabolism.