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Background <p>Glioblastoma (GBM) has an extremely poor prognosis. Abnormal mitochondrial function, metabolic disorders, and dysregulated ferroptosis all drive its malignant progression, and the underlying molecular regulatory mechanisms still need further clarification. This study focuses on the regulatory mechanisms linking mitochondrial function, lipid metabolism, and ferroptosis to provide new directions for clinical treatment.</p> Methods <p>Bioinformatics analysis confirmed aberrant upregulation of mitochondrial ribosomal protein L36 (MRPL36) in GBM, correlating with poor prognosis. In vitro and in vivo assays validated its roles in regulating GBM cell proliferation and invasion. RNA sequencing and untargeted metabolomics were used to analyze molecular changes upon MRPL36 knockdown. Acyl-biotin exchange (ABE) assays examined MRPL36 regulation of zinc finger DHHC-type palmitoyltransferase 12 (ZDHHC12)-mediated glutathione peroxidase 4 (GPX4) palmitoylation. Co-immunoprecipitation (Co-IP), Western blotting and mass spectrometry (MS) characterized tripartite motif-containing 33 (TRIM33)-dependent K48-linked ubiquitination and proteasomal degradation of GPX4 under MRPL36 modulation. The molecular network driving GBM progression was ultimately clarified.</p> Results <p>MRPL36 is highly expressed in GBM and associated with poor patient prognosis. Silencing MRPL36 exacerbates mitochondrial damage and disturbs lipid metabolism homeostasis. It suppresses ZDHHC12-mediated GPX4 palmitoylation, promotes TRIM33-mediated GPX4 K48-linked ubiquitination and degradation, induces ferroptosis in GBM cells, and markedly inhibits tumor proliferation, invasion, and in vivo growth. Ferroptosis inhibitors partially reverse these inhibitory effects, confirming that MRPL36 regulates GBM progression by balancing GPX4 palmitoylation and ubiquitination.</p> Conclusion <p>This study confirms that MRPL36, as a key regulatory factor in GBM progression, maintains mitochondrial function and lipid metabolism homeostasis, modulates the balance between GPX4 palmitoylation (mediated by ZDHHC12) and ubiquitination (mediated by TRIM33), inhibits ferroptosis, and promotes GBM malignant progression, providing new targets and theoretical basis for GBM precise treatment.</p>

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Dual regulation of metabolic reprogramming and protein competitive modifications: the core role and mechanism of MRPL36 in glioblastoma malignant progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Haonan Ye,
  • Yuqi Wen,
  • Zhihua Chen,
  • Lei Wu,
  • Zhe Zhang,
  • Jie Zeng,
  • Siyi Zhao,
  • Bowen Fan,
  • Bin Liao,
  • Xinyu Tu,
  • Zhangda Xiong,
  • Lieliang Zhang,
  • Youyi Xia,
  • Jun Xie,
  • Hong Zhu,
  • Hua Guo,
  • Feng Xiao

摘要

Background

Glioblastoma (GBM) has an extremely poor prognosis. Abnormal mitochondrial function, metabolic disorders, and dysregulated ferroptosis all drive its malignant progression, and the underlying molecular regulatory mechanisms still need further clarification. This study focuses on the regulatory mechanisms linking mitochondrial function, lipid metabolism, and ferroptosis to provide new directions for clinical treatment.

Methods

Bioinformatics analysis confirmed aberrant upregulation of mitochondrial ribosomal protein L36 (MRPL36) in GBM, correlating with poor prognosis. In vitro and in vivo assays validated its roles in regulating GBM cell proliferation and invasion. RNA sequencing and untargeted metabolomics were used to analyze molecular changes upon MRPL36 knockdown. Acyl-biotin exchange (ABE) assays examined MRPL36 regulation of zinc finger DHHC-type palmitoyltransferase 12 (ZDHHC12)-mediated glutathione peroxidase 4 (GPX4) palmitoylation. Co-immunoprecipitation (Co-IP), Western blotting and mass spectrometry (MS) characterized tripartite motif-containing 33 (TRIM33)-dependent K48-linked ubiquitination and proteasomal degradation of GPX4 under MRPL36 modulation. The molecular network driving GBM progression was ultimately clarified.

Results

MRPL36 is highly expressed in GBM and associated with poor patient prognosis. Silencing MRPL36 exacerbates mitochondrial damage and disturbs lipid metabolism homeostasis. It suppresses ZDHHC12-mediated GPX4 palmitoylation, promotes TRIM33-mediated GPX4 K48-linked ubiquitination and degradation, induces ferroptosis in GBM cells, and markedly inhibits tumor proliferation, invasion, and in vivo growth. Ferroptosis inhibitors partially reverse these inhibitory effects, confirming that MRPL36 regulates GBM progression by balancing GPX4 palmitoylation and ubiquitination.

Conclusion

This study confirms that MRPL36, as a key regulatory factor in GBM progression, maintains mitochondrial function and lipid metabolism homeostasis, modulates the balance between GPX4 palmitoylation (mediated by ZDHHC12) and ubiquitination (mediated by TRIM33), inhibits ferroptosis, and promotes GBM malignant progression, providing new targets and theoretical basis for GBM precise treatment.