METTL16 suppresses ferroptosis in cholangiocarcinoma by promoting ATF4 via m 6 A modification.

Autor:	Zhao S; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Cao J; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Liang R; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Peng T; Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Wu S; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Liu Z; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Wu Y; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Song L; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China.; Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China., Sun C; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Liu Y; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Gu J; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Wang L; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Zhu R; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Wang W; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China., Sun Y; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.; Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, China.
Jazyk:	angličtina
Zdroj:	International journal of biological sciences [Int J Biol Sci] 2025 Jan 01; Vol. 21 (1), pp. 189-203. Date of Electronic Publication: 2025 Jan 01 (Print Publication: 2025).
DOI:	10.7150/ijbs.97886
Abstrakt:	Background: N6-methyladenosine (m 6 A) modification is the most common post-transcriptional modifications, which is critical for the metabolism of ferroptosis-related RNAs. Yet, the impact of m 6 A 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 Fe 2+ 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. Competing Interests: Competing Interests: The authors have declared that no competing interest exists. (© The author(s).)
Databáze:	MEDLINE
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