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<p>Misfolded proteins cause or contribute to a wide range of progressive diseases that are difficult to treat. Desmin-related (cardio-)myopathy (DRM), a well-studied proteinopathy, presents with progressive muscle weakness and shortened life span. Most DRM patients display intracellular accumulation of desmin and its chaperone αB-crystallin (CRYAB). Using an unbiased high-throughput screen, we found that Janus kinase 1 (JAK1) knockdown resulted in lower CRYAB<sup>R120G</sup> aggregates in cardiomyocytes. Here, we tested whether the JAK1/2 inhibitor ruxolitinib ameliorates the disease phenotype in CRYAB<sup>R120G</sup> DRM models. Ruxolitinib cleared pre-existing CRYAB<sup>R120G</sup> aggregates in neonatal rat cardiomyocytes and human induced-pluripotent stem cell-derived cardiomyocytes, and enhanced ubiquitin-proteasome system (UPS)-mediated degradation. Blocking UPS function and specifically knockdown of the E3 ligase ASB2 blunted the effect of ruxolitinib on CRYAB<sup>R120G</sup> accumulation. In DRM mice, phospho-STAT3 and JAK1 levels were higher than in non-transgenic mice, indicating pathologically active JAK-STAT signaling. Ruxolitinib treatment resulted in lower CRYAB<sup>R120G</sup> aggregate load and prevented cardiac dysfunction in DRM mice. Similar findings were obtained by crossing DRM mice with the cardiomyocyte-specific <i>Jak1</i> knockout, suggesting JAK1 as a therapeutic target in proteinopathy.</p>

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JAK1/2 inhibitor ruxolitinib reduces aggregates in cardiac proteinopathy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月31日

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  • Erda Alizoti,
  • Leonie Ewald,
  • Simona Parretta,
  • Jacob J K March,
  • Moritz Meyer-Jens,
  • Ellen Orthey,
  • Christian Conze,
  • Lucie Carrier,
  • Jeffrey Robbins,
  • Sonia R Singh

摘要

Misfolded proteins cause or contribute to a wide range of progressive diseases that are difficult to treat. Desmin-related (cardio-)myopathy (DRM), a well-studied proteinopathy, presents with progressive muscle weakness and shortened life span. Most DRM patients display intracellular accumulation of desmin and its chaperone αB-crystallin (CRYAB). Using an unbiased high-throughput screen, we found that Janus kinase 1 (JAK1) knockdown resulted in lower CRYABR120G aggregates in cardiomyocytes. Here, we tested whether the JAK1/2 inhibitor ruxolitinib ameliorates the disease phenotype in CRYABR120G DRM models. Ruxolitinib cleared pre-existing CRYABR120G aggregates in neonatal rat cardiomyocytes and human induced-pluripotent stem cell-derived cardiomyocytes, and enhanced ubiquitin-proteasome system (UPS)-mediated degradation. Blocking UPS function and specifically knockdown of the E3 ligase ASB2 blunted the effect of ruxolitinib on CRYABR120G accumulation. In DRM mice, phospho-STAT3 and JAK1 levels were higher than in non-transgenic mice, indicating pathologically active JAK-STAT signaling. Ruxolitinib treatment resulted in lower CRYABR120G aggregate load and prevented cardiac dysfunction in DRM mice. Similar findings were obtained by crossing DRM mice with the cardiomyocyte-specific Jak1 knockout, suggesting JAK1 as a therapeutic target in proteinopathy.