Phosphoproteomics distinguishes disease-specific mechanisms for human phospholamban cardiomyopathy reversible by RNA therapy.
FE, D., N, B., P, D., D, S., AN, L., IB, D., KF, A.G., A, E.G., J, Z., & A, W. (2026). Phosphoproteomics distinguishes disease-specific mechanisms for human phospholamban cardiomyopathy reversible by RNA therapy.. Signal transduction and targeted therapy. https://doi.org/10.1038/s41392-026-02791-5
FE D, N B, P D, D S, AN L, IB D, et al. Phosphoproteomics distinguishes disease-specific mechanisms for human phospholamban cardiomyopathy reversible by RNA therapy.. Signal transduction and targeted therapy. 2026; doi: 10.1038/s41392-026-02791-5
FE D, N B, P D, et al. Phosphoproteomics distinguishes disease-specific mechanisms for human phospholamban cardiomyopathy reversible by RNA therapy.[J]. Signal transduction and targeted therapy. 2026. DOI: 10.1038/s41392-026-02791-5.
@article{fe2026,
author = {Deiman FE and Bömer N and Davidsson P and Später D and Linders AN and Dias IB and Arevalo Gomez KF and Esquivel Gaytan A and Zhu J and Walentinsson A},
title = {Phosphoproteomics distinguishes disease-specific mechanisms for human phospholamban cardiomyopathy reversible by RNA therapy.},
journal = {Signal transduction and targeted therapy},
year = {2026},
doi = {10.1038/s41392-026-02791-5},
note = {PMID: 42204136},
}
TY - JOUR AU - Deiman FE AU - Bömer N AU - Davidsson P AU - Später D AU - Linders AN AU - Dias IB AU - Arevalo Gomez KF AU - Esquivel Gaytan A AU - Zhu J AU - Walentinsson A TI - Phosphoproteomics distinguishes disease-specific mechanisms for human phospholamban cardiomyopathy reversible by RNA therapy. T2 - Signal transduction and targeted therapy PY - 2026 DO - 10.1038/s41392-026-02791-5 AN - PMID:42204136 ER -
Phospholamban (PLN) p.Arg14del (R14Δ/+, also known as R14del) is a pathogenic variant that causes inherited cardiomyopathy. RNA therapy improves cardiac function and survival in murine PLN R14Δ/+. However, the molecular disease mechanisms and potential therapeutic effects of RNA therapy in the human setting remain poorly defined. Proteomic and phosphoproteomic profiling was performed on cardiac tissue from R14Δ/+ patients (N = 6) and compared to other causes of dilated cardiomyopathy (DCM; N = 10). Findings were validated in CRISPR-Cas9-engineered R14Δ/+ induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and isogenic controls. To assess reversibility, PLN-targeted RNA therapy using antisense oligonucleotides was applied to iPSC-CMs. Proteomics revealed enrichment of fibrotic pathways, while phosphoproteomics highlighted altered actomyosin structural organization uniquely distinguishing R14Δ/+ from other DCM. This phosphoproteomic profile was recapitulated in R14Δ/+ iPSC-CMs. RNA therapy concentration-dependently reduced PLN expression and modified the disease-specific phosphorylation profile. Twenty-eight phosphorylation sites were consistently altered across patient tissue and iPSC-CMs; twenty-two were reversed by RNA therapy and were enriched for cadherin- and actin-binding functions, implicating cytoskeletal remodeling. PLN/LC3 protein aggregates, a hallmark of PLN cardiomyopathy, were reduced after RNA therapy. Functionally, R14Δ/+ cardiomyocytes exhibited accelerated calcium handling and contractile kinetics, which increased further upon RNA therapy. Human PLN R14Δ/+ cardiomyopathy is characterized by a distinct phosphoproteomic signature involving cytoskeletal and contractile machinery. PLN-targeted RNA therapy reduced PLN expression, partially normalized these alterations, diminished protein aggregation, and enhanced calcium handling and contractile performance. These findings clarify the molecular mechanisms underlying R14Δ/+ pathogenesis and support RNA therapy as a promising therapeutic strategy for PLN cardiomyopathy.