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Objective <p>This study investigates the role of m6A regulators in invasive pituitary neuroendocrine tumors (PitNETs) by defining m6A-related molecular subtypes, constructing a nomogram, and elucidating the mechanistic role of METTL14 in PitNET progression.</p> Methods <p>GEO datasets were analyzed for m6A regulatory gene expression. Machine learning approaches were used to develop a nomogram. m6A molecular and gene subtypes were identified, and scRNA-seq from tumors characterized intratumoral subpopulations. Functional validation was performed using METTL14 overexpression and knockdown in PitNET cells, followed by proliferation, invasion, RT-qPCR, Western blotting, m6A-RIP, RIP, RNA stability, and luciferase reporter assays.</p> Results <p>Seven key m6A regulators were selected for the nomogram. Two m6A subtypes were identified, with Cluster B showing lower immune infiltration and higher m6A scores. Further classification revealed two gene-based subtypes with consistent patterns. scRNA-seq defined four PitNET clusters, including a proliferative TPC population with the highest invasion scores, strongly correlated with METTL14. Functional experiments confirmed that METTL14 promotes proliferation, invasion, and autophagy via PI3K/AKT activation. Mechanistically, IGF2 was identified as a novel downstream effector of METTL14, as METTL14 enhanced IGF2 expression through m6A modification, thereby activating PI3K/AKT signaling.</p> Conclusion <p>This study provides a comprehensive characterization of m6A methylation in invasive PitNET, integrating bulk and single-cell transcriptomics. The nomogram offers clinical potential, while the discovery of TPCs and the identification of the METTL14–IGF2–PI3K/AKT regulatory axis highlight novel mechanistic insights and therapeutic targets for personalized invasive PitNET management.</p>

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Single-cell and machine learning approaches reveal METTL14-mediated autophagy via PI3K/AKT signaling in invasive PitNET

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月26日

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  • Shuangjian Yang,
  • Changqin Pu,
  • Congcong Deng,
  • Xuexue Bai,
  • Chenxin Tian,
  • Wentai Zhang,
  • Kan Deng,
  • Lian Duan,
  • Lin Lu,
  • Huijuan Zhu,
  • Yong Yao,
  • Renzhi Wang,
  • Mengqi Chang,
  • Ming Feng

摘要

Objective

This study investigates the role of m6A regulators in invasive pituitary neuroendocrine tumors (PitNETs) by defining m6A-related molecular subtypes, constructing a nomogram, and elucidating the mechanistic role of METTL14 in PitNET progression.

Methods

GEO datasets were analyzed for m6A regulatory gene expression. Machine learning approaches were used to develop a nomogram. m6A molecular and gene subtypes were identified, and scRNA-seq from tumors characterized intratumoral subpopulations. Functional validation was performed using METTL14 overexpression and knockdown in PitNET cells, followed by proliferation, invasion, RT-qPCR, Western blotting, m6A-RIP, RIP, RNA stability, and luciferase reporter assays.

Results

Seven key m6A regulators were selected for the nomogram. Two m6A subtypes were identified, with Cluster B showing lower immune infiltration and higher m6A scores. Further classification revealed two gene-based subtypes with consistent patterns. scRNA-seq defined four PitNET clusters, including a proliferative TPC population with the highest invasion scores, strongly correlated with METTL14. Functional experiments confirmed that METTL14 promotes proliferation, invasion, and autophagy via PI3K/AKT activation. Mechanistically, IGF2 was identified as a novel downstream effector of METTL14, as METTL14 enhanced IGF2 expression through m6A modification, thereby activating PI3K/AKT signaling.

Conclusion

This study provides a comprehensive characterization of m6A methylation in invasive PitNET, integrating bulk and single-cell transcriptomics. The nomogram offers clinical potential, while the discovery of TPCs and the identification of the METTL14–IGF2–PI3K/AKT regulatory axis highlight novel mechanistic insights and therapeutic targets for personalized invasive PitNET management.