JAK1/2 inhibitor ruxolitinib reduces aggregates in cardiac proteinopathy
Summary
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. © 2026. The Author(s).
| Authors | Alizoti E, Ewald L, Parretta S, March JJK, Meyer-Jens M, Orthey E, Conze C, Carrier L, Robbins J, Singh SR |
|---|---|
| Journal | EMBO molecular medicine |
| Publication Date | 2026 May;18(5):1836-1865 |
| PubMed | 41917326 |
| PubMed Central | PMC13179346 |
| DOI | 10.1038/s44321-026-00411-x |