ORCID Identifier(s)

0009-0006-9625-9069

Graduation Semester and Year

Summer 2026

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering

Department

Bioengineering

First Advisor

Jun Liao

Second Advisor

Zhi-Ping Liu

Third Advisor

Young-Tae Kim

Fourth Advisor

Juhyun Lee

Fifth Advisor

Xiankai Sun

Abstract

Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiac disorders, affecting a substantial proportion of the population and remaining a leading cause of sudden cardiac death (SCD) in young individuals and athletes. The disease is characterized by a constellation of pathological features, including myocardial hypertrophy, interstitial and replacement fibrosis, and a heightened susceptibility to life-threatening arrhythmias. While the genetic basis of HCM-most commonly arising from mutations in sarcomere genes such as MYH7-has been well established, and current therapeutic strategies have accordingly focused on modulating sarcomere function directly, this approach addresses only one dimension of a disease process that is likely far more complex. In particular, the contribution of epigenetic dysregulation to the initiation and progression of HCM has received comparatively little attention, despite growing evidence that chromatin-level changes may underlie much of the transcriptional reprogramming observed in diseased myocardium.

This gap in understanding represents both a conceptual limitation in the field and a missed therapeutic opportunity. To address this, we investigated the therapeutic potential of JIB-04, a pan–histone lysine demethylase (KDM) inhibitor, using a murine model harboring the equivalent of the pathogenic human MYH7 R403Q mutation (Myh6403/+ mice). Our results demonstrate that JIB-04 exerts broad and durable protective effects across multiple stages and models of disease. In a cyclosporin-A–accelerated model of HCM, treatment prevented disease progression, significantly reduced both hypertrophy and fibrosis, preserved overall cardiac function, and notably eliminated SCD, an outcome with direct clinical relevance given that SCD remains one of the most feared and difficult-to-predict complications of HCM. Beyond this preventive effect, JIB-04 also proved capable of reversing already-established disease, and the benefits of treatment persisted even after drug withdrawal, suggesting a sustained or self-reinforcing therapeutic effect rather than one contingent on continuous pharmacological suppression. Furthermore, in aged mice exhibiting spontaneous, naturally occurring HCM, JIB-04 treatment improved cardiac function, extending the relevance of these findings beyond genetically accelerated or induced disease models to a context more closely resembling age-related human disease progression.

To characterize the molecular basis of these effects, we performed transcriptomic and chromatin accessibility analyses, which revealed that JIB-04 treatment partially restored disease-associated chromatin accessibility profiles and normalized associated gene transcriptional programs-providing direct mechanistic evidence that the observed phenotypic benefits are underpinned by epigenetic remodeling rather than downstream compensatory effects alone. Through this analysis, we identified PHF2 (KDM7C) as a candidate mediator of JIB-04's therapeutic action, a finding consistent across both mouse and human HCM hearts. Functional validation confirmed the relevance of this target: knockdown of PHF2 suppressed hypertrophic gene expression programs in cardiomyocytes, inflammatory programs in macrophages, and fibrotic programs in fibroblasts, indicating that PHF2 contributes to disease pathology across multiple cell types within the diseased myocardium rather than acting through a single cellular compartment.

Supporting the translational relevance of this pathway, human HCM hearts showed elevated expression of several JIB-04 sensitive KDMs, including PHF2 itself, reinforcing the possibility that this mechanism is conserved in human disease. Consistent with this, in human induced pluripotent stem cell-derived cardiomyocytes carrying the MYH7-R403Q mutation, JIB-04 normalized disease-associated transcriptional signatures, restored proper connexin-43 localization-a protein critical for electrical coupling between cardiomyocytes and, by extension, arrhythmia risk-and improved mitochondrial function, further substantiating the translational potential of this approach in a human cellular system. Despite these encouraging findings, prolonged JIB-04 treatment was associated with reversible hepatomegaly accompanied by hepatic lipid accumulation, an important safety signal that must be accounted for in any future therapeutic development. Encouragingly, co-administration of the antioxidant N-acetylcysteine mitigated this liver toxicity while preserving the drug's cardiac efficacy, indicating that the on-target cardiac benefits and off-target hepatic effects may be mechanistically separable and, therefore, manageable through rational combination therapy. Taken together, these findings establish histone lysine demethylase inhibition as a promising and mechanistically distinct epigenetic therapeutic strategy for HCM, one capable of addressing hypertrophy, fibrosis, arrhythmic risk, and SCD across multiple disease stages and models. These results support the continued development of KDM-targeted therapies, both as a novel treatment avenue for HCM and as a broader proof of concept for epigenetic intervention in inherited cardiac disease.

Keywords

Hypertrophic cardiomyopathy (HCM), Epigenetics, Histone lysine demethylases (KDMs), JIB-04, MYH7 R403Q, PHF2 (KDM7C), Cardiac remodeling, Fibrosis, Sudden cardiac death (SCD), N-acetylcysteine (NAC)

Disciplines

Molecular, Cellular, and Tissue Engineering

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