Targeting STK39 ameliorates cardiac remodeling by Improving Mitochondrial function through degradation of IFIT3

ABSTRACT:

Pathological cardiac remodeling in response to sustained pressure overload is a pivotal process in the progression of heart failure (HF), yet the underlying molecular mechanisms remain incompletely understood, limiting therapeutic development. Here, we identify serine/threonine kinase 39 (STK39) as a critical mediator across this remodeling progression, showing its marked upregulation in both hypertrophic and failing human hearts, as well as in mouse hearts after transverse aortic constriction. Cardiomyocyte-specific Stk39 knockdown ameliorates cardiac hypertrophy, improves ventricular function, and attenuates myocardial fibrosis in vivo, while STK39 silencing suppresses angiotensin II (Ang II)-induced hypertrophic growth, fibrosis, and mitochondrial dysfunction in mice cardiomyocytes in vitro. Integrated multi-omics and experimental validation identify interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) as a key downstream target. Mechanistically, STK39 physically interacts with IFIT3 and competes with the E2/E3 ligase UBE2O for binding, thereby protecting IFIT3 from UBE2O-mediated ubiquitination and degradation. Stabilized of IFIT3 impairs mitochondrial homeostasis via VDAC2, promoting mitochondrial reactive oxygen species (ROS) production, which triggers Ca2+ dysregulation and subsequent Calcineurin/NFATc3 activation, ultimately driving pathological gene transcription and cardiac remodeling. Collectively, our findings uncover a reveal a previously unrecognized novel function of STK39 and establish the STK39-IFIT3 axis that links mitochondrial dysregulation to classical hypertrophic signaling, positioning this axis as a potential therapeutic target for pressure overload-induced HF.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

PROVIDER: MTBLS15834 | MetaboLights | 2026-09-28

REPOSITORIES: MetaboLights