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<p>Metastatic clear cell renal cell carcinoma (ccRCC) remains lethal due to therapy resistance, and while dysregulated Wnt/β-catenin signaling drives progression, its post-translational regulation is poorly understood. Through multi-omics analysis of TCGA/GEO datasets, we identified MAGI3 as a key metastasis suppressor in ccRCC. Functional validation revealed that MAGI3 loss enhances invasion, migration and metastatic potential in vitro and in vivo. Mechanistically, MAGI3 binds β-catenin’s C-terminus via PDZ domains, disrupting intramolecular N-terminus–ARM domain interactions to expose phosphorylation sites, thereby enabling GSK-3β–mediated β-catenin phosphorylation and ubiquitin-dependent degradation. Critically, low MAGI3 hyperactivates β-catenin and drives mTOR inhibitor resistance. Combining Everolimus with the Wnt inhibitor XAV-939 slashed viability and invasion in resistant cells. Clinically, patients whose tumors exhibited high MAGI3 and low β-catenin expression demonstrated significantly improved response to Everolimus therapy. In conclusion, MAGI3 is a critical gatekeeper of β-catenin destruction in ccRCC. Its loss defines a metastatic, therapy-resistant subtype targetable by dual mTOR/Wnt blockade. Therefore, MAGI3 expression may stratify patients for personalized therapy.</p><p></p>

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MAGI3 deficiency unleashes β-catenin conformational change to drive metastatic progression and mTOR inhibitor resistance in ccRCC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Siyu Gu,
  • Haibo Wang,
  • Hua Liu,
  • Yumeng Yang,
  • Yu Guo,
  • Pengyan Fa,
  • Lijie Zhang,
  • Yang Yang,
  • Xuan Qi,
  • Qiong Qin,
  • Ran Song,
  • Xiaomei Yang,
  • Junqi He

摘要

Metastatic clear cell renal cell carcinoma (ccRCC) remains lethal due to therapy resistance, and while dysregulated Wnt/β-catenin signaling drives progression, its post-translational regulation is poorly understood. Through multi-omics analysis of TCGA/GEO datasets, we identified MAGI3 as a key metastasis suppressor in ccRCC. Functional validation revealed that MAGI3 loss enhances invasion, migration and metastatic potential in vitro and in vivo. Mechanistically, MAGI3 binds β-catenin’s C-terminus via PDZ domains, disrupting intramolecular N-terminus–ARM domain interactions to expose phosphorylation sites, thereby enabling GSK-3β–mediated β-catenin phosphorylation and ubiquitin-dependent degradation. Critically, low MAGI3 hyperactivates β-catenin and drives mTOR inhibitor resistance. Combining Everolimus with the Wnt inhibitor XAV-939 slashed viability and invasion in resistant cells. Clinically, patients whose tumors exhibited high MAGI3 and low β-catenin expression demonstrated significantly improved response to Everolimus therapy. In conclusion, MAGI3 is a critical gatekeeper of β-catenin destruction in ccRCC. Its loss defines a metastatic, therapy-resistant subtype targetable by dual mTOR/Wnt blockade. Therefore, MAGI3 expression may stratify patients for personalized therapy.