DR8 (DHNNPQIR), a rapeseed-derived peptide, mitigates fibrosis and muscle atrophy in chronic kidney disease by targeting CNR1-ERK/ELK-1 signaling.

DR8 (DHNNPQIR) is a rapeseed-derived bioactive octapeptide with antioxidant and anti-inflammatory properties, but its therapeutic potential in chronic kidney disease (CKD) and related muscle wasting has not been defined. In this study, we investigated the anti-fibrotic and anti-atrophic efficacy of DR8 using complementary in vitro, transcriptomic, and in vivo approaches. In TGF-β1-stimulated C2C12 myoblasts and HK-2 tubular epithelial cells, DR8 significantly attenuated fibrosis and atrophy by downregulating cannabinoid receptor 1 (CNR1) and suppressing ERK-ELK1 activation, leading to restoration of myogenic regulators (MYOD, MYOG) and inhibition of proteolytic E3 ligases (MuRF-1, MAFbx). Transcriptomic analysis identified CNR1 as a key upstream target mediating these effects. In a 5/6 nephrectomized (5/6Nx) mouse model, systemic administration of DR8 significantly improved renal function, reduced collagen accumulation, and alleviated skeletal muscle fibrosis and atrophy, accompanied by suppression of CNR1-ERK-ELK1 activation in both organs. Together, these findings demonstrate that DR8 exerts strong renoprotective and myoprotective effects through selective modulation of CNR1-dependent signaling pathways, supporting its potential as a novel peptide therapeutic for CKD-associated fibrosis and muscle wasting.