The novel ErbB4 agonist JK07 modulates gene expression in key cardiac cells. insights from single-nuclei transcriptomics in a murine heart failure model

Heart failure (HF) involves complex interactions among cardiac cell types that drive disease progression. The neuregulin (NRG-1)/ErbB pathway is critical for cardiac repair, but clinical use of NRG-1 is limited by poor stability and receptor specificity. JK07, a fusion of an anti-ErbB3 antibody and the EGF-like domain, selectively activates ErbB4 while blocking ErbB3 activation to reduce side effects. While JK07 has demonstrated early promise in the treatment of HF clinically, its cellular mechanisms underpinning these effects remain unclear. This study explores how JK07 impact on gene expression across key cardiac cell populations.

We hypothesized that JK07 modulates gene expression in key cardiac cell types, inducing distinct molecular responses depending on treatment duration.

BALB/c mice with MI-induced HF (EF<40%) received either a single or four weekly doses of JK07 (1 mg/kg) or vehicle. Hearts were collected 1 and 7 days after treatment for the single-dose experiments, or 7 and 28 days after the last dose for the four-dose experiments. Assessments included echocardiography, heart weight, histology, and single-nuclei RNA sequencing.

JK07 promoted cardiac recovery by reducing interstitial fibrosis and increasing capillary density in multi-dose groups. Transcriptomic profiling revealed robust, cell-specific gene modulation, particularly one day after injection. In cardiomyocytes, JK07 transiently increased ErbB4 expression, reversed HF-associated transcriptional changes, and induced metabolic reprogramming with enhanced mitochondrial and lipid-metabolic pathways. Fibroblasts shifted toward reparative phenotypes, including activation of anti-fibrotic Htra3-TGF-β-Igfbp7 signaling. Endothelial cells demonstrated early activation of angiogenic and cytoskeletal programs. Cell-cell communication mapping showed early amplification of fibroblast-centered reparative networks and later suppression of pro-fibrotic signaling. In vitro, JK07 preserved mitochondrial respiration under TNF-α presence.

JK07 promotes cardiac repair by driving cell-type-specific transcriptional programs that support metabolic adaptation in cardiomyocytes, modulate ErbB4-high fibroblast functions, and enhance endothelial regeneration. These findings highlight the therapeutic potential and support its further development as a therapeutic strategy for HF.Figure 1For image description, please refer to the figure legend and surrounding text.  Figure 2For image description, please refer to the figure legend and surrounding text.