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

ABSTRACT: 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 kl/kl 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 in vivo rescued hepatic integrity, res

SUBMITTER: Tan H 

PROVIDER: S-EPMC12837819 | biostudies-literature | 2026

REPOSITORIES: biostudies-literature