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Peer-reviewedCC BY-NC-ND 4.0Cellular & Molecular Biology Letters

miR-4652-5p targets GFPT1 to suppress ATF6-mediated unfolded protein response (UPR) and UPR-driven apoptosis to drive gastric tumor progression

  • Qingyu Zeng1,2
  • Yangyuan Huang1,2
  • Liping Li1,2
  • Shihao Liang1,2
  • Wenjie Liao1,2
  • Weiyan Li1,2
  • Bin Li1,2
  • Bing Wei1,3
  1. 1Department of Gastroenterology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi People’s Republic of China
  2. 2Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi People’s Republic of China
  3. 3College of International of Guilin Medical University, Guilin, Guangxi People’s Republic of China
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Abstract

Background: The equilibrium of the endoplasmic reticulum (ER) is vital for ensuring regular cellular operations. However, diverse pathological stimuli can disrupt ER proteostasis, leading to ER stress and ultimately triggering programmed cell death. Ongoing stress in the ER activates the unfolded protein response (UPR), an adaptive signaling mechanism aimed at reestablishing ER protein stability and aiding tumor cell survival in harsh microenvironmental conditions. Yet, the mechanisms through which key UPR regulators operate in this adaptive process are still not fully known.

Methods: We investigated the role of miR-4652-5p in gastric cancer (GC) by quantifying its expression in clinical GC tissue samples. This was followed by modulating miR-4652-5p expression in GC cell lines via knockdown and overexpression. The effects on malignant phenotypes were evaluated via various methods, such as Cell Counting Kit 8 (CCK-8) proliferation assays, colony formation assays, wound healing assays, and Transwell migration assays. Transcriptome sequencing analysis suggested that miR-4652-5p plays a role in controlling the UPR and apoptosis. Experimental validation through qPCR, dual-luciferase reporter assays, and western blotting confirmed that miR-4652-5p aids in GC tumor progression by modulating UPR and apoptosis via a GFPT1-dependent mechanism affecting ATF6.

Results: We identified elevated expression of miR-4652-5p in GC, which correlated with unfavorable patient prognosis. Studies conducted with GC cell lines and clinical tissue specimens revealed that miR-4652-5p acts as an oncogene in GC by enhancing tumor cell growth and migration while also suppressing cell death. Transcriptome sequencing performed on miR-4652-5p–overexpressing cells revealed a pronounced association with the UPR. Mechanistically, miR-4652-5p attenuates ATF6 expression, thereby restraining excessive UPR activation and subsequent apoptosis—an effect likely mediated through its interaction with GFPT1.

Conclusions: For the first time, we identified a novel regulatory axis in the UPR in which miR-4652-5p reduces both ATF6 expression and its proapoptotic effects by targeting GFPT1. This investigation identified miR-4652-5p as a novel and promising target for GC treatment.

Graphical abstract:

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s11658-026-01002-x.

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Cite

BibTeXRIS
BibTeX
@article{zeng2026mir46525p,
  title = {{miR-4652-5p targets GFPT1 to suppress ATF6-mediated unfolded protein response (UPR) and UPR-driven apoptosis to drive gastric tumor progression}},
  author = {Qingyu Zeng and Yangyuan Huang and Liping Li and Shihao Liang and Wenjie Liao and Weiyan Li and Bin Li and Bing Wei},
  journal = {Cellular \& Molecular Biology Letters},
  year = {2026},
  month = jul,
  doi = {10.1186/s11658-026-01002-x},
  url = {https://doi.org/10.1186/s11658-026-01002-x},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - miR-4652-5p targets GFPT1 to suppress ATF6-mediated unfolded protein response (UPR) and UPR-driven apoptosis to drive gastric tumor progression
AU  - Qingyu Zeng
AU  - Yangyuan Huang
AU  - Liping Li
AU  - Shihao Liang
AU  - Wenjie Liao
AU  - Weiyan Li
AU  - Bin Li
AU  - Bing Wei
PY  - 2026
DA  - 2026/07/27
JO  - Cellular & Molecular Biology Letters
DO  - 10.1186/s11658-026-01002-x
UR  - https://doi.org/10.1186/s11658-026-01002-x
AB  - Background: The equilibrium of the endoplasmic reticulum (ER) is vital for ensuring regular cellular operations. However, diverse pathological stimuli can disrupt ER proteostasis, leading to ER stress and ultimately triggering programmed cell death. Ongoing stress in the ER activates the unfolded protein response (UPR), an adaptive signaling mechanism aimed at reestablishing ER protein stability and aiding tumor cell survival in harsh microenvironmental conditions. Yet, the mechanisms through which key UPR regulators operate in this adaptive process are still not fully known.  Methods: We investigated the role of miR-4652-5p in gastric cancer (GC) by quantifying its expression in clinical GC tissue samples. This was followed by modulating miR-4652-5p expression in GC cell lines via knockdown and overexpression. The effects on malignant phenotypes were evaluated via various methods, such as Cell Counting Kit 8 (CCK-8) proliferation assays, colony formation assays, wound healing assays, and Transwell migration assays. Transcriptome sequencing analysis suggested that miR-4652-5p plays a role in controlling the UPR and apoptosis. Experimental validation through qPCR, dual-luciferase reporter assays, and western blotting confirmed that miR-4652-5p aids in GC tumor progression by modulating UPR and apoptosis via a GFPT1-dependent mechanism affecting ATF6.  Results: We identified elevated expression of miR-4652-5p in GC, which correlated with unfavorable patient prognosis. Studies conducted with GC cell lines and clinical tissue specimens revealed that miR-4652-5p acts as an oncogene in GC by enhancing tumor cell growth and migration while also suppressing cell death. Transcriptome sequencing performed on miR-4652-5p–overexpressing cells revealed a pronounced association with the UPR. Mechanistically, miR-4652-5p attenuates ATF6 expression, thereby restraining excessive UPR activation and subsequent apoptosis—an effect likely mediated through its interaction with GFPT1.  Conclusions: For the first time, we identified a novel regulatory axis in the UPR in which miR-4652-5p reduces both ATF6 expression and its proapoptotic effects by targeting GFPT1. This investigation identified miR-4652-5p as a novel and promising target for GC treatment.  Graphical abstract:  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s11658-026-01002-x.
SN  - 1425-8153
SN  - 1689-1392
ER  -