ALDOA‐Mediated Metabolic Reprogramming is a Targetable Vulnerability for Ferroptosis Sensitization in Cancer

Abstract Ferroptosis presents great potential for cancer therapy, either alone or in combination with classical therapy. However, inducing ferroptosis by targeting canonical ferroptosis suppressors that directly inhibit lipid peroxidation non‐selectively induces ferroptosis in both cancerous and normal cells, thereby limiting its therapeutic potential. In this study, it is revealed that aldolase A (ALDOA) reprograms lipid metabolism to resist ferroptosis in cancer cells and identifies ALDOA as a targetable vulnerability for ferroptosis sensitization. Cancer cells with ALDOA suppression exhibit increased susceptibility to ferroptosis—a response less obvious in normal cells. Mechanistically, ALDOA depletion induces significant accumulation of fructose 1,6‐bisphosphate in cancer cells, thereby enhancing autophagy‐dependent degradation of phospholipid‐modifying enzymes. These alterations increase the ratio of phospholipids containing pro‐ferroptotic polyunsaturated fatty acids over anti‐ferroptotic monounsaturated fatty acids, culminating in heightened ferroptosis sensitivity. Moreover, ALDOA inhibitors selectively promote ferroptosis in cancer cells, both in vitro and in vivo. Collectively, the findings reveal that ALDOA‐mediated metabolic reprogramming is a targetable vulnerability for ferroptosis sensitization in cancer.