Nuclear Factor Kappa‐B Inducing Kinase‐ and Inhibitor of Nuclear Factor Kappa‐B Kinase Subunit Beta‐Binding Protein Promotes Pathological Cardiac Hypertrophy by Regulating Inhibitor of Nuclear Factor Kappa‐B Kinase Subunit Beta‐Mediated Nuclear Factor Kappa‐B Activation

Background Pathological cardiac hypertrophy is a major risk factor for heart failure. NIBP (NF‐κB [nuclear factor kappa‐B] inducing kinase‐ and inhibitor of NF‐κB kinase subunit beta‐binding protein) is a key regulator of cytokine‐induced NF‐κB signaling, but its role in cardiac hypertrophy remains unknown. Methods We established transverse aortic constriction‐induced cardiac hypertrophy in mice and phenylephrine‐induced hypertrophy in neonatal rat ventricular myocytes. Genetic interventions included generation of whole‐body Nibp knockout mice via CRISPR‐Cas9; creation of cardiomyocyte‐specific Nibp knockout mice using adeno‐associated virus serotype 9‐delivered Cre and single‐guide RNAs in Rosa26‐LSL‐Cas9 mice; and cardiac‐specific Nibp overexpression via adeno‐associated virus serotype 9delivery. In neonatal rat ventricular myocytes, NIBP was knocked down or overexpressed using adenoviruses. Phenotypes were assessed by echocardiography, histology (wheat germ agglutinin, picrosirius redstaining), and molecular analyses. Mechanisms were investigated via RNA‐sequencing, coimmunoprecipitation, and Western blotting for key signaling molecules. Results NIBP protein was upregulated in hypertrophic hearts and cardiomyocytes. Both Nibp ‐knockout and cardiomyocyte‐specific Nibp knockout attenuated transverse aortic constriction‐induced cardiac dysfunction, hypertrophy, and fibrosis, whereas Nibp overexpression exacerbated these pathologies. Consistently, in neonatal rat ventricular myocytes, NIBP knockdown mitigated, while its overexpression aggravated, phenylephrine‐induced cardiomyocyte hypertrophy and inflammatory responses. Mechanistically, NIBP directly interacted with IKKβ (inhibitor of NF‐κB kinase subunit beta), enhanced its phosphorylation, and drove hyperactivation of the downstream NF‐κB pathway. Overexpression of a kinase‐dead IKKβ mutant reversed the hypertrophic effects of NIBP. Conclusions NIBP promotes pathological cardiac hypertrophy by activating the IKKβ/NF‐κB axis, identifying it as a potential therapeutic target for cardiac remodeling and heart failure.