Regulatory mechanism of O-linked N-acetylglucosamine protein modification on autophagy in cancer - Review

Sep 22, 2026

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O-linked N-acetylglucosamine protein modification (O-GlcNAcylation) is described as a nutrient- and stress-sensitive post-translational switch that is frequently upregulated in cancers. Autophagy is presented as a lysosome-dependent recycling pathway with context-dependent roles in tumorigenesis and therapy resistance. The review consolidates emerging evidence that O-GlcNAcylation and autophagy cross-regulate through stage-specific effects on autophagy initiation, maturation, and fusion. It highlights targets including ULK1, LC3 lipidation, SNAP-29 and signaling nodes such as mTOR and AMPK, and discusses therapeutic opportunities to disrupt the O-GlcNAc–autophagy axis.

LanguageEnglish

CategoryResearch & Report

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Pages18

Reading Time45 min

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DOI: 10.1002/ctm2.70596 REVIEW Regulatory mechanism of O-linked N-acetylglucosamine protein modification on autophagyin cancer Yizhan Li1,2, 3 Ling Gao1,2, 3 Shaoming Li1,2, 3 Jingjing Zheng4 Keqian Zhi1,2, 3 Wenhao Ren1, 3 1 Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, Qingdao, China 2 School ofStomatology, Qingdao University, Qingdao, China 3 Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China 4 Department ofStomatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China Correspondence Wenhao Ren, Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao 266003, Shandong, China. [Email:](Email: herohao@163.com)[ herohao@163.com](Email: herohao@163.com) Keqian Zhi, Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao 266003, Shandong, China. [Email:](Email: zhikeqian@sina.com)[ zhikeqian@sina.com](Email: zhikeqian@sina.com) Graphical Abstract ∙ O-GlcNAcylation serves as a nutrient and stress sensor that dynamically regulates autophagy at multiple stages in cancer cells. ∙ It fine-tunes autophagy initiation, maturation and fusion by modifying key proteins such as ULK1, ATG4B and SNAP-29 . ∙ Context-dependent O-GlcNAcylation promotes tumour adaptation and therapy resistance via autophagy remodelling. ∙ Targeting the O-GlcNAc–autophagy axis offers a promising strategy to overcome cancer drug resistance. Clin. Transl. Med. 2026;16:e70596 . [https://doi.org/10.1002/ctm2.70596](https://doi.org/10.1002/ctm2.70596) [wileyonlinelibrary.com/journal/ctm2](wileyonlinelibrary.com/journal/ctm2) DOI: 10.1002/ctm2.70596 REVIEW Regulatory mechanism of O-linked N-acetylglucosamine protein modification on autophagyin cancer Yizhan Li1,2, 3 Ling Gao1,2, 3 Shaoming Li1,2, 3 Jingjing Zheng4 Keqian Zhi1,2, 3 Wenhao Ren1, 3 1 Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, Qingdao, China 2 School ofStomatology, Qingdao University, Qingdao, China 3 Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China 4 Department ofStomatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China Correspondence Wenhao Ren, Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao 266003, Shandong, China. [Email:](Email: herohao@163.com)[ herohao@163.com](Email: herohao@163.com) Keqian Zhi, Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Distract, Qingdao 266003, Shandong, China. Email: [zhikeqian@sina.com](zhikeqian@sina.com) Funding information National Natural Science Foundation of China, Grant/Award Numbers: 42176096, 42176097; Natural Science Foundation of Shandong Province, Grant/Award Number: ZR2021MD065; TaiShan Scholars Foundation of Shandong Province, Grant/Award Number: tsqn202306397 Abstract Background: O-linked N-acetylglucosamine protein modification (OGlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification frequently upregulated in cancers. Autophagy, a lysosome-dependent recycling pathway, plays a context-dependent dual role in tumorigenesis and therapy resistance. Emerging evidence reveals intricate crosstalk between these two processes, positioning the O-GlcNAcylation-autophagy axis as a critical regulator of cancer cell adaptation. Main Topics: This review systematically delineates the multidimensional mechanisms by which O-GlcNAcylation regulates distinct stages of autophagy initiation, maturation, and fusion across various cancer types. We detail how O-GlcNAcylation targets core autophagy

FAQs

What role does O-GlcNAcylation play in cancer autophagy?

O-GlcNAcylation dynamically regulates autophagy at multiple stages and influences pro-tumor or tumor-suppressive outcomes depending on context. It is linked to tumor adaptation and resistance via autophagy remodeling.

Which autophagy components and signaling hubs are highlighted as O-GlcNAcylation targets?

The review emphasizes targeting core autophagy machinery such as the ULK1 complex, the LC3 lipidation system, and SNARE fusion proteins including SNAP-29. It also notes modulation of mTOR and AMPK.

How could targeting the O-GlcNAc–autophagy axis help overcome drug resistance?

Combining small-molecule inhibitors of O-GlcNAc cycling enzymes (OGT/OGA) with autophagy modulators is proposed as a strategy to reduce tumor drug resistance. The rationale is to interfere with the regulatory network that supports survival and therapeutic escape.

Sep 22, 2026

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