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

Yunyi Bian, Guangyao Shan, Guoshu Bi, Zhijie Xu, Jiaqi Liang, Yuanliang Yan, Wei Guo, Qihai Sui, Yanjun Yi, Haochun Shi, Tao Lu, Huan Zhang, Qun Wang, Hong Fan (), Wei Jiang () and Cheng Zhan ()
Additional contact information
Yunyi Bian: Fudan University
Guangyao Shan: Fudan University
Guoshu Bi: Fudan University
Zhijie Xu: Central South University
Jiaqi Liang: Fudan University
Yuanliang Yan: Central South University
Wei Guo: Peking Union Medical College
Qihai Sui: Fudan University
Yanjun Yi: Fudan University
Haochun Shi: Fudan University
Tao Lu: Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University
Huan Zhang: University of Electronic Science and Technology of China
Qun Wang: Fudan University
Hong Fan: Fudan University
Wei Jiang: Fudan University
Cheng Zhan: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65441-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65441-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65441-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().