2. Academic Validation
  3. METTL16 suppresses ferroptosis in cholangiocarcinoma by promoting ATF4 via m6A modification

METTL16 suppresses ferroptosis in cholangiocarcinoma by promoting ATF4 via m6A modification

  • Int J Biol Sci. 2025 Jan 1;21(1):189-203. doi: 10.7150/ijbs.97886.
Senfeng Zhao 1 2 3,  Jiahui Cao 1 2 3,  Ruopeng Liang 1 2 3,  Tingting Peng 4,  Shitao Wu 1 2 3,  Zhipu Liu 1 2 3,  Yahui Wu 1 2 3,  Liming Song 1 2 3 5,  Chenguang Sun 1 2 3,  Yin Liu 1 2 3,  Junmou Gu 1 2 3,  Libo Wang 1 2 3,  Rongtao Zhu 1 2 3,  Weijie Wang 1 2 3,  Yuling Sun 1 2 3
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 2 Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.
  • 3 Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China.
  • 4 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
PMID: 39744432 DOI: 10.7150/ijbs.97886
Abstract

Background: N6-methyladenosine (m6A) modification is the most common post-transcriptional modifications, which is critical for the metabolism of ferroptosis-related RNAs. Yet, the impact of m6A modification on Ferroptosis in cholangiocarcinoma (CC) is far from clear. Methods: Public databases and tissue arrays were applied to explore the clinical relevance of METTL16 in CC. Then, the effects of METTL16 on growth and Ferroptosis were studied in vitro and in vivo. Mechanistically, RNA-sequencing, methylated RNA immunoprecipitation, dual-luciferase reporter assays and RNA stability assays were used to identify the METTL16/ATF4 axis in Ferroptosis in CC. Results: Clinically, we find that METTL16 is overexpressed and associated with a poor prognosis in patients with CC. Functionally, METTL16 protects against Ferroptosis by maintaining mitochondrial homeostasis, including mitochondrial structure, membrane potential and energy products. It also decreases cellular metabolism of Fe2+ and lipid peroxide, thereby promoting cell growth in vitro and in vivo. Mechanistically, ATF4 is a novel target of METTL16 and METTL16 enhances the m6A level and expression of ATF4 mRNA by inhibiting its decay, which further prevented Ferroptosis in CC via m6A modification. Conclusions: Our findings highlighted the role of METTL16/ATF4 in Ferroptosis, which sheds light on potential therapeutic strategies for CC.

Keywords

ATF4; METTL16; cholangiocarcinoma; ferroptosis; m6A.

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