What question did this study set out to answer?

Investigate the role of IL-8-mediated signaling in hypertrophic cardiomyopathy associated with Noonan syndrome.

April 18, 2026Open Access

Targeting Interleukin-8–Mediated Cellular Crosstalk Reverses Hypertrophic Cardiomyopathy and Cardiac Fibrosis in Noonan Syndrome

Key Result

Targeting aberrant IL-8-CXCR1 signaling reverses hypertrophic cardiomyopathy and cardiac fibrosis, offering a potential therapeutic option for patients with Noonan syndrome.

Key Points

Investigate the role of IL-8-mediated signaling in hypertrophic cardiomyopathy associated with Noonan syndrome.
Utilized two-dimensional and three-dimensional human induced pluripotent stem cell models of LZTR1 deficiency
Analyzed cells and tissues from patients with Noonan syndrome with pathogenic RAS-MAPK variants on multiple levels
Employed reparixin to inhibit IL-8-CXCR1 signaling and evaluate effects on cardiomyocytes and fibroblasts
Cytokine-mediated crosstalk between cardiac fibroblasts and cardiomyocytes drives hypertrophic cardiomyopathy development
IL-8 secretion induced fibrosis, increased tissue stiffness, and cardiomyocyte hypertrophy
Reparixin successfully reversed the pathological effects associated with dysregulated IL-8 signaling

Structured PICO

Does targeting IL-8-CXCR1 signaling reverse hypertrophic cardiomyopathy and cardiac fibrosis in Noonan Syndrome?

Population

Models of Noonan Syndrome-associated hypertrophic cardiomyopathy

Intervention

Targeting IL-8-CXCR1 signaling

Outcome

Reversal of hypertrophic cardiomyopathy and cardiac fibrosissurrogate

Targeting IL-8-CXCR1 signaling represents a novel potential therapeutic strategy for reversing hypertrophic cardiomyopathy and cardiac fibrosis in Noonan Syndrome.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

BACKGROUND: Genetic variants in components or regulators of the RAS-MAPK signaling pathway are causative for severe and early-onset hypertrophic cardiomyopathy (HCM) in patients with Noonan syndrome (NS). Despite paracrine communication being considered to play a pivotal role in the etiology of cardiomyopathies, there is a paucity of knowledge about the underlying pathomechanism that leads to the development of hypertrophic cardiomyopathy and cardiac fibrosis in NS. METHODS: To dissect the impact of noncardiomyocytes in the development of NS, we employed two-dimensional and three-dimensional human induced pluripotent stem cell models of LZTR1 deficiency alongside induced pluripotent stem cells derived from patients with NS with pathogenic variants in key RAS-MAPK genes and analyzed these cells and tissues at the molecular, cellular, and functional levels. RESULTS: Our findings revealed that cytokine-mediated cellular crosstalk between cardiac fibroblasts and cardiomyocytes, predominantly activated in the disease state, serves as a primary driver of the disease. Cardiac fibroblast-specific IL-8 (interleukin-8) secretion induced fibrosis-related signatures, tissue stiffness, cardiomyocyte hypertrophy, and hypercontractility, identifying dysregulated IL-8 as a heart-autonomous signaling molecule independent of inflammation and immune cell involvement. Inhibition of IL-8-CXCR1 signaling by reparixin reversed the pathological effects in cardiac fibroblasts and cardiomyocytes. CONCLUSIONS: These data provide evidence that targeting aberrant IL-8-CXCR1 signaling may be an effective therapeutic option for patients with NS-associated hypertrophic cardiomyopathy.