2. Academic Validation
  3. Targeting polyamine metabolism and ferroptosis enhances the efficacy of KRAS-targeted therapy depending on KEAP1 status

Targeting polyamine metabolism and ferroptosis enhances the efficacy of KRAS-targeted therapy depending on KEAP1 status

  • Nat Commun. 2025 Nov 11;16(1):9923. doi: 10.1038/s41467-025-65441-4.
Yunyi Bian # 1 2,  Guangyao Shan # 1,  Guoshu Bi # 1,  Zhijie Xu 3,  Jiaqi Liang 1,  Yuanliang Yan 4,  Wei Guo 5,  Qihai Sui 1,  Yanjun Yi 1,  Haochun Shi 1,  Tao Lu 6,  Huan Zhang 7,  Qun Wang 1,  Hong Fan 8 9,  Wei Jiang 10,  Cheng Zhan 11 12 13
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4 Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 5 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
  • 6 Department of Thoracic Surgery, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China.
  • 7 Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital& Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China.
  • 8 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 9 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China. [email protected].
  • 10 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 11 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 12 Department of Thoracic Surgery, ShangHai Geriatric Medicine Center, Shanghai, China. [email protected].
  • 13 Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41219185 DOI: 10.1038/s41467-025-65441-4
Abstract

The resistance to KRAS-targeted therapies, particularly due to co-occurring gene mutations, remains a significant challenge. Through a metabolite library screening, we reveal that polyamines sensitize KRAS inhibitors only in KRASMU/KEAP1WT cells but not in KRASMU/KEAP1MU cells. Transcriptome Sequencing and metabolome profiling pinpoint SAT1, the key enzyme in polyamine metabolism, as essential for this divergence. In KRASMU/KEAP1WT context, treatment of KRAS inhibitors activates JNK/c-Jun pathway and SAT1 expression, while the augmented SAT1 facilitates polyamine metabolism and KRAS inhibitors-induced Ferroptosis. Conversely, in KRASMU/KEAP1MU cells, activated JNK promotes the degradation of NRF2, thereby inhibiting SAT1 expression. Our results further demonstrate that polyamine supplementation enhances KRAS-targeted therapy in KRASMU/KEAP1WT resistant cells, patient-derived organoids, xenografts, and spontaneously tumorigenic mice, while KRASMU/KEAP1MU models require lentivirus or adeno-associated virus-mediated SAT1 overexpression prior to polyamine treatment, to augment Ferroptosis and drug sensitivity. Our findings highlight SAT1-mediated polyamine metabolism as a promising target in precision treatments for KRAS-mutant cancers.

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