Targeting the undruggable transcription factor, KLF5, with a peptidomimetic small molecule, NC114, attenuates pressure overload-induced cardiac remodeling and fibrosis.

Krüppel-like factor 5 (KLF5) is an intrinsically disordered transcription factor involved in cardiac remodeling, cancer, and metabolic diseases. Targeting KLF5 has been a persistent challenge in drug development due to its structural inaccessibility. We investigated cardioprotective effects of NC114, a rationally designed small molecule that mimics a short, hydrophobic α-helical motif in KLF5, thereby disrupting its protein–protein interactions. Adult C57BL/6J male mice underwent transverse aortic constriction (TAC) or sham surgery, followed by administration of NC114 or vehicle. NC114-treated TAC mice exhibited preserved cardiac function, reduced heart weight-to-body weight ratio, and markedly attenuated interstitial fibrosis. Gene expression analysis demonstrated decreased cardiac expression of Klf5, Nppb, Tgfb1, PAI-1, Col1a1, and Fn1. NC114 also suppressed oxidative stress and reduced phosphorylation of PKCδ and expression of HIF-1α during the early phase post-TAC. Metabolomic profiling revealed that NC114 treatment reversed TAC-induced accumulation of organic and amino acids. NC114, a novel peptidomimetic molecule, targets the undruggable transcription factor KLF5 to attenuate cardiac hypertrophy, fibrosis, and metabolic dysregulation in pressure overload-induced heart failure. This study highlights the potential of KLF5 inhibition as a therapeutic strategy in cardiovascular disease.