Lysine-arginine imbalance overcomes therapeutic tolerance governed by the transcription factor E3-lysosome axis in glioblastoma

Yongwei Jing, Masahiko Kobayashi, Mahmoud I. Shoulkamy, Meiqi Zhou, Ha Vu, Hiroshi Arakawa, Hemragul Sabit, Sadahiro Iwabuchi, Cong Quang Vu, Atsuko Kasahara, Masaya Ueno, Yuko Tadokoro, Kenta Kurayoshi, Xi Chen, Yuhang Yan, Satoshi Arai, Shinichi Hashimoto, Tomoyoshi Soga, Tomoki Todo, Mitsutoshi Nakada and Atsushi Hirao ()
Additional contact information
Yongwei Jing: Kanazawa University
Masahiko Kobayashi: Kanazawa University
Mahmoud I. Shoulkamy: Kanazawa University
Meiqi Zhou: Kanazawa University
Ha Vu: Kanazawa University
Hiroshi Arakawa: Kanazawa University
Hemragul Sabit: Kanazawa University
Sadahiro Iwabuchi: Wakayama Medical University
Cong Quang Vu: Kanazawa University
Atsuko Kasahara: Kanazawa University
Masaya Ueno: Kanazawa University
Yuko Tadokoro: Kanazawa University
Kenta Kurayoshi: Kanazawa University
Xi Chen: Kanazawa University
Yuhang Yan: Kanazawa University
Satoshi Arai: Kanazawa University
Shinichi Hashimoto: Wakayama Medical University
Tomoyoshi Soga: Keio University
Tomoki Todo: The University of Tokyo
Mitsutoshi Nakada: Kanazawa University
Atsushi Hirao: Kanazawa University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Recent advances in cancer therapy have underscored the importance of targeting specific metabolic pathways. In this study, we propose a precision nutrition approach aimed at lysosomal function in glioblastoma multiforme (GBM). Using patient-derived GBM cells, we identify lysosomal activity as a unique metabolic biomarker of tumorigenesis, controlling the efficacy of temozolomide (TMZ), a standard GBM therapy. Employing combined analyses of clinical patient samples and xenograft models, we further elucidate the pivotal role of Transcription Factor Binding To IGHM Enhancer 3 (TFE3), a master regulator of lysosomal biogenesis, in modulating malignant properties, particularly TMZ tolerance, by regulating peroxisome proliferator-activated receptor-gamma coactivator 1−alpha (PGC1α)-mediated mitochondrial activity. Notably, we find that lysine protects GBM cells from lysosomal stress by counteracting arginine’s effects on nitric oxide production. The lysine restriction mimetic, homoarginine administration, significantly enhances the efficacy of anticancer therapies through lysosomal dysfunction. This study underscores the critical role of lysosomal function modulated by amino acid metabolism in GBM pathogenesis and treatment.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-56946-z 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_s41467-025-56946-z

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

DOI: 10.1038/s41467-025-56946-z

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 ().