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Background <p>Cushing’s disease (CD) is a clinical syndrome caused by excessive secretion of adrenocorticotropic hormone (ACTH) from a pituitary corticotroph adenoma, resulting in adrenal cortical hyperplasia and overproduction of cortisol. The T-box transcription factor (TPIT) is crucial for regulating ACTH secretion in pituitary corticotroph adenomas. This study aims to explore the ubiquitin-mediated degradation of TPIT and identify potential pharmaceutical agents for treating CD.</p> Methods <p>The TPIT-interacting protein STUB1 was identified via mass spectrometry. The interaction between STUB1 and TPIT was confirmed using NanoBiT and GST pulldown assays. The expression of TPIT, pro-opiomelanocortin (POMC), and STUB1 was assessed by immunoblotting, dual-luciferase reporter assays, quantitative real-time PCR, RNA-sequencing, and immunohistochemistry. ACTH levels were measured by ELISA.</p> Results <p>STIP1 Homology and U-Box Containing Protein 1 (STUB1) interacts with TPIT through its TPR domain and ubiquitinates multiple sites on TPIT via the U-box domain, leading to TPIT degradation. This degradation reduces POMC expression and ACTH secretion in AtT-20 cells. Additionally, STUB1 inhibits cell proliferation both in vitro and in vivo. Clinical investigations revealed that STUB1 expression is significantly lower in ACTH-secreting corticotroph adenomas than in silent corticotroph adenomas (SCAs). A negative correlation was observed between STUB1 and TPIT protein levels, as well as POMC expression. Furthermore, NanoBiT drug screening identified that Irbesartan and Lumiracoxib increased TPIT degradation, thereby reducing POMC expression and ACTH secretion.</p> Conclusion <p>STUB1 is a promising therapeutic target for CD and drugs targeting the STUB1-TPIT complex may provide a potential treatment approach.</p> Graphical Abstract <p>E3 ubiquitin ligase STUB1 interacts with TPIT, mediating its ubiquitination degradation, subsequently inhibiting POMC transcription and ATCH secretion. Irbesartan and Lumiracoxib can promote TPIT degradation and suppress ACTH secretion by enhancing the interaction between STUB1 and TPIT.</p>

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The STUB1-TPIT axis regulates the secretion of adrenocorticotrophic hormone in cushing disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • Fang Liu,
  • Yanting Liu,
  • Tao Zhang,
  • Ning Huang,
  • Desheng Chen,
  • Xiaobin Wang,
  • Jiangong Ma,
  • Li Xue,
  • Shaojian Lin,
  • Zhe Bao Wu

摘要

Background

Cushing’s disease (CD) is a clinical syndrome caused by excessive secretion of adrenocorticotropic hormone (ACTH) from a pituitary corticotroph adenoma, resulting in adrenal cortical hyperplasia and overproduction of cortisol. The T-box transcription factor (TPIT) is crucial for regulating ACTH secretion in pituitary corticotroph adenomas. This study aims to explore the ubiquitin-mediated degradation of TPIT and identify potential pharmaceutical agents for treating CD.

Methods

The TPIT-interacting protein STUB1 was identified via mass spectrometry. The interaction between STUB1 and TPIT was confirmed using NanoBiT and GST pulldown assays. The expression of TPIT, pro-opiomelanocortin (POMC), and STUB1 was assessed by immunoblotting, dual-luciferase reporter assays, quantitative real-time PCR, RNA-sequencing, and immunohistochemistry. ACTH levels were measured by ELISA.

Results

STIP1 Homology and U-Box Containing Protein 1 (STUB1) interacts with TPIT through its TPR domain and ubiquitinates multiple sites on TPIT via the U-box domain, leading to TPIT degradation. This degradation reduces POMC expression and ACTH secretion in AtT-20 cells. Additionally, STUB1 inhibits cell proliferation both in vitro and in vivo. Clinical investigations revealed that STUB1 expression is significantly lower in ACTH-secreting corticotroph adenomas than in silent corticotroph adenomas (SCAs). A negative correlation was observed between STUB1 and TPIT protein levels, as well as POMC expression. Furthermore, NanoBiT drug screening identified that Irbesartan and Lumiracoxib increased TPIT degradation, thereby reducing POMC expression and ACTH secretion.

Conclusion

STUB1 is a promising therapeutic target for CD and drugs targeting the STUB1-TPIT complex may provide a potential treatment approach.

Graphical Abstract

E3 ubiquitin ligase STUB1 interacts with TPIT, mediating its ubiquitination degradation, subsequently inhibiting POMC transcription and ATCH secretion. Irbesartan and Lumiracoxib can promote TPIT degradation and suppress ACTH secretion by enhancing the interaction between STUB1 and TPIT.