Work

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

Year: 2025

Type: article

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.

Source: Advanced Science

DOI: 10.1002/advs.202511880