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

## TL;DR

This study shows that targeting ALDOA makes cancer cells more vulnerable to ferroptosis, a type of cell death, without harming normal cells.

## Contribution

ALDOA is identified as a novel target for sensitizing cancer cells to ferroptosis through metabolic reprogramming.

## Key findings

- ALDOA suppression increases ferroptosis susceptibility in cancer cells but not in normal cells.
- ALDOA depletion enhances autophagy-dependent degradation of phospholipid-modifying enzymes.
- ALDOA inhibitors promote ferroptosis in cancer cells both in vitro and in vivo.

## 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.

ALDOA‐depletion‐mediated glycolytic reprogramming promotes autophagy‐mediated degradation of MBOAT2, increasing the ratio of phospholipids containing pro‐ferroptotic polyunsaturated fatty acids over anti‐ferroptotic monounsaturated fatty acids, and thus sensitizing cancer cells to ferroptosis. Targeting this metabolic cascade reveals a cancer‐specific vulnerability that can be exploited for safe and effective ferroptosis‐based therapy.