DLAT sustains redox homeostasis and prevent colorectal cancer from ferroptosis by regulating SLC25A39-mediated mitochondrial glutathione transport

  • Free Radic Biol Med. 2026 Aug 1:251:229-242. doi: 10.1016/j.freeradbiomed.2026.04.133.
Kun Zhang  1 ,  Xin Zhang  2 ,  Chenqi Huang  2 ,  Junyi Yang  2 ,  Longxuan Dong  2 ,  Xijing Chen  3 ,  Chen Xun  4 ,  Yongjian Guo  5
Affiliations
  • 1. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, #639 Longmian Avenue, Nanjing, 211198, China.
  • 2. Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China.
  • 3. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, #639 Longmian Avenue, Nanjing, 211198, China. Electronic address: [email protected].
  • 4. Nanjing Tianyinshan Hospital and the First Affiliated Hospital of China Pharmaceutical University, #3789 Jiyin Rd, Nanjing, 211112, China. Electronic address: [email protected].
  • 5. School of Biopharmacy, China Pharmaceutical University, #639 Longmian Avenue, Nanjing, 211198, China. Electronic address: [email protected].
PMID: 42009144 DOI: 10.1016/j.freeradbiomed.2026.04.133
Abstract

Colorectal Cancer (CRC) remains a leading cause of cancer-related mortality, with limited therapeutic options for advanced-stage patients. Here, we identify DLAT, a key enzyme in Mitochondrial Metabolism, as a critical driver of CRC progression. Multi-omics analyses revealed that DLAT was overexpressed in CRC tissues and correlated with poor patient prognosis. The results showed that DLAT promoted CRC growth by promoting the resistance to mitochondrial antioxidant stress and suppressing Ferroptosis. Mechanistically, DLAT directly bond to the mitochondrial glutathione (mtGSH) transporter SLC25A39 and enhanced its protein stability independent of intracellular GSH levels, leading to the maintain of mitochondrial GSH (mtGSH) import and redox homeostasis. Knockdown of DLAT or SLC25A39 disrupted mtGSH transport, elevated lipid peroxidation, and sensitized CRC cells to Ferroptosis. We further identified a small molecular drug GL-V9 as a DLAT degrader. GL-V9 bond to DLAT and induced DLAT degradation through ubiquitin-proteasome pathway. The disruption of DLAT-SLC25A39 axis by GL-V9 led to mtGSH depletion and oxidative stress, as well as the significant suppression of CRC growth. These findings establish DLAT as a metabolic vulnerability in CRC and highlight GL-V9 as a promising therapeutic agent.

Keywords
Colorectal cancer; DLAT; GL-V9; Mitochondrial GSH transport; SLC25A39.
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