CCN5-Derived Peptide Ameliorates Liver Fibrosis in Mice through Inhibiting the ERK1/2 and PI3K Signaling Pathways

Liver fibrosis is a pathological process characterized by the activation of hepatic stellate cells (HSCs) and the excessive accumulation of extracellular matrix (ECM) proteins. Cellular communication network 5 (CCN5) has been recently recognized for its ability to counteract the profibrotic effects of CCN2 in fibrotic diseases. Herein, we report the discovery of a CCN5-derived peptide CDP199 that effectively suppresses HSC activation and reduces ECM protein deposition. Notably, CDP199 exhibits strong inhibitory effects on HSC proliferation and migration. The subsequent <i>in vivo</i> study demonstrated that peptide CDP199 significantly alleviates liver injury, enhances liver function, and mitigates liver fibrosis in a carbon tetrachloride-induced mouse model. Mechanistically, CDP199 inhibits the phosphorylation of ERK1/2 and PI3K both <i>in vitro</i> and <i>in vivo</i>. These findings highlight the therapeutic potential of CCN5-derived peptides, specifically CDP199, as a promising antifibrotic candidate for treating liver diseases through inhibition of ERK1/2 and PI3K signaling pathways.