JAK1/2 inhibitor ruxolitinib reduces aggregates in cardiac proteinopathy

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Updated: Apr 2, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

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Erda Alizoti1,2, Leonie Ewald1,2, Simona Parretta1,2

  • 1Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

EMBO Molecular Medicine
|March 31, 2026
PubMed

Insights

Janus kinase 1 (JAK1) inhibition with ruxolitinib reduces toxic protein aggregates in desmin-related (cardio-)myopathy (DRM) models. This JAK1 targeting approach clears protein buildup and prevents cardiac dysfunction, offering a potential therapeutic strategy for proteinopathies.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Protein Biochemistry

Background:

  • Protein misfolding causes progressive, difficult-to-treat diseases like desmin-related (cardio-)myopathy (DRM).
  • DRM is characterized by intracellular accumulation of desmin and its chaperone αB-crystallin (CRYAB).
  • JAK-STAT signaling is implicated in proteinopathies.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting Janus kinase 1 (JAK1) in CRYAB-associated DRM.
  • To determine if ruxolitinib, a JAK1/2 inhibitor, can ameliorate DRM phenotypes.

Main Methods:

  • High-throughput screening identified JAK1 knockdown as reducing CRYAB aggregates.
  • Tested ruxolitinib in cardiomyocyte and mouse models of CRYAB-R120G DRM.
  • Assessed aggregate clearance, ubiquitin-proteasome system (UPS) function, and cardiac function.
  • Utilized cardiomyocyte-specific Jak1 knockout mice.

Main Results:

  • Ruxolitinib cleared existing CRYAB aggregates and enhanced UPS-mediated degradation in vitro.
  • Blocking UPS or ASB2 knockdown blunted ruxolitinib's aggregate-clearing effect.
  • DRM mice exhibited elevated phospho-STAT3 and JAK1 levels.
  • Ruxolitinib treatment reduced CRYAB aggregates and prevented cardiac dysfunction in DRM mice.
  • Cardiomyocyte-specific Jak1 knockout mirrored ruxolitinib's protective effects.

Conclusions:

  • JAK1 signaling is pathologically active in DRM and contributes to CRYAB aggregate accumulation.
  • Ruxolitinib effectively reduces protein aggregates and prevents cardiac dysfunction in DRM models.
  • JAK1 represents a promising therapeutic target for treating proteinopathies like DRM.
Keywords:
ASB2CRYABDesminJAK1Ruxolitinib

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