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<p>Proteasome inhibitor (PI) resistance remains a major barrier in the treatment of multiple myeloma (MM), underscoring the urgent need to elucidate underlying mechanisms and identify actionable therapeutic targets. Here, we uncover METTL16 as a regulator of MM progression and PI sensitivity via an m6A methyltransferase activity–independent mechanism of translational control. Mechanistically, METTL16 overexpression is associated with altered PERK–eIF2α interaction and reduced eIF2α phosphorylation, accompanied by increased translation of key transcripts, including PSMB5 and CCND1. Consistently, these translational outputs coincide with increased proteasome activity and proliferative capacity. Notably, pharmacological targeting of METTL16 enhances the efficacy of multiple PIs in MM cells. These findings not only expand the functional landscape of METTL16 beyond RNA methylation, but also suggest that METTL16 represents a potential target for improving PI-based therapy in MM.</p><p></p>

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METTL16 enhances proteasome inhibitor resistance in multiple myeloma by inhibiting eIF2α-PERK interaction and promoting PSMB5 translation

  • 期刊论文

  • 发表日期：

    2026年3月13日

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  • Guanli Wang,
  • Xuejie Gao,
  • Hui Zhang,
  • Ke Hu,
  • Qilin Feng,
  • Yujie Liu,
  • Chaolu Hu,
  • Shushan Guo,
  • Dandan Yu,
  • Shuaikang Chang,
  • Xiaosong Wu,
  • Xinyan Jia,
  • Dong An,
  • Yu Peng,
  • Yi Tao,
  • Haiyan Cai,
  • Gege Chen,
  • Li Zhang,
  • Jumei Shi

摘要

Proteasome inhibitor (PI) resistance remains a major barrier in the treatment of multiple myeloma (MM), underscoring the urgent need to elucidate underlying mechanisms and identify actionable therapeutic targets. Here, we uncover METTL16 as a regulator of MM progression and PI sensitivity via an m6A methyltransferase activity–independent mechanism of translational control. Mechanistically, METTL16 overexpression is associated with altered PERK–eIF2α interaction and reduced eIF2α phosphorylation, accompanied by increased translation of key transcripts, including PSMB5 and CCND1. Consistently, these translational outputs coincide with increased proteasome activity and proliferative capacity. Notably, pharmacological targeting of METTL16 enhances the efficacy of multiple PIs in MM cells. These findings not only expand the functional landscape of METTL16 beyond RNA methylation, but also suggest that METTL16 represents a potential target for improving PI-based therapy in MM.