2. Academic Validation
  3. The UFL1-AKT positive feedback loop promotes breast cancer progression by enhancing lipid synthesis

The UFL1-AKT positive feedback loop promotes breast cancer progression by enhancing lipid synthesis

  • Nat Commun. 2026 Jan 20;17(1):614. doi: 10.1038/s41467-026-68492-3.
Fei Meng # 1,  Yating Du # 1,  Junjie Liang # 2,  Huiyan Li 1,  Jingjing Wang 1,  Kexin Tang 1,  Ruixue Kong 1,  Huanran Sun 3,  Tingting Yin 1,  Junru Qin 1,  Xiaomeng Yang 1,  Changliang Shan 3,  Min Liu 1,  Guiwen Yang 1,  Jichun Zhang 4,  Yijie Wang 5,  Jun Zhou 6 7,  Yan Chen 8
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Center for Cell Structure and Function, Modern Industry Institute of Biomedicine, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China.
  • 2 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
  • 3 College of Pharmacy, Nankai University, Tianjin, China.
  • 4 Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 5 Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Center for Cell Structure and Function, Modern Industry Institute of Biomedicine, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China. [email protected].
  • 6 Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Center for Cell Structure and Function, Modern Industry Institute of Biomedicine, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China. [email protected].
  • 7 College of Life Sciences, Nankai University, Tianjin, China. [email protected].
  • 8 Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Center for Cell Structure and Function, Modern Industry Institute of Biomedicine, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China. [email protected].
  • # Contributed equally.
PMID: 41559041 DOI: 10.1038/s41467-026-68492-3
Abstract

UFMylation, a ubiquitin-like modification, is crucial for cellular processes and is linked to human diseases, including Cancer. However, its role in Cancer remains unclear. Here, we report that UFL1 promotes breast tumor growth by remodeling lipid metabolism. Mechanistically, UFL1 interacts with and UFMylates Akt, enhancing its localization at the endoplasmic reticulum and phosphorylation by PDK1 and mTORC2, thereby increasing AKT-mediated lipid synthesis. Moreover, Akt phosphorylates UFL1, boosting its activity. Thus, UFL1 and Akt form a positive feedback loop, accelerating lipid synthesis and breast tumor growth. Clinically, UFL1 levels are increased in human breast tumors and are associated with poor clinical outcomes in breast Cancer patients. Importantly, UFMylation inhibitors sensitize breast Cancer cells to Akt inhibitors and Anticancer drugs. Our findings reveal a critical role for UFMylation in lipid metabolism and identify the UFL1-AKT axis as a potential therapeutic target in breast Cancer.

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