Klotho-derived peptide 1 ameliorates hepatic fibrosis induced by αKlotho deficiency and liver injury

Hepatic fibrosis, driven primarily by hepatic stellate cells (HSCs) activation induced by TGF-β, currently lacks effective therapies. In this study, we demonstrated that deficiency of αKlotho, an extrahepatic antiaging protein, due to genetic ablation in <i>kl/kl</i> model or aging caused spontaneous hepatic fibrosis, as evidenced by an increased collagens deposition and TGF-β signaling hyperactivation. KP1, a small peptide derived from human αKlotho protein, recapitulated its anti-fibrotic potential and blocked HSCs activation induced by TGF-β1. Mechanistically, KP1 acted as a competitive TGF-β receptor 2 (TβR2) antagonist, disrupted TGF-β1/TβR2 engagement, and suppressed both canonical and noncanonical TGF-β signaling in HSCs. Infusion of KP1 <i>in vivo</i> rescued hepatic integrity, restored liver function, inhibited TGF-β signaling and mitigated hepatic fibrosis in <i>kl/kl</i> mice. In mouse model of carbon tetrachloride-induced hepatic fibrosis, KP1 exhibited preferential accumulation in injured liver after intravenous injection, disrupted TGF-β1/TβR2 interaction, inhibited HSCs activation, and ameliorated hepatic fibrosis. Similarly, KP1 also mitigated cholestatic fibrosis induced by bile duct ligation. Collectively, these studies establish KP1 as a novel, mechanism-driven therapeutic peptide that potently inhibits HSCs activation and liver fibrogenesis. Its liver-targeted delivery and efficacy across diverse fibrosis models underscore KP1 as a promising next-generation therapeutic remedy for fibrotic liver disease.