Work

Identification of an effective treatment for liver fibrosis based on a long acting easy to deliver TNF-α-derived peptide

Year: 2025

Type: article

Abstract: Tumor necrosis factor α (TNF-α) is an attractive anti-liver fibrosis drug because of its cell apoptosis-inducing ability on activated hepatic stellate cells (HSCs) via TNF-α receptor 1 (TNFR1). However, the application of TNF-α has been limited by its short half-life, poor targeting capacity and promotion of cell proliferation via TNF-α receptor 2 (TNFR2). TNF-α-derived peptide, P16, specific induces cell apoptosis by its binding to TNFR1 but not TNFR2. Endogenous IgG-based controlled release is an ideal strategy for extending the serum half-life via FcRn-mediated recycling, and platelet-derived growth factor receptor β (PDGFRβ)-mediated endocytosis improves fibrotic liver-targeting potential because of its overexpression on activated HSCs. Herein, we designed a tridomain Z-IgBD-P16, by sequentially fusing a PDGFRβ-specific affibody Z PDGFRβ and two repeats of IgG-binding domain (IgBD) to the N-terminus of P16. Z PDGFRβ -mediated binding of Z-IgBD-P16 to PDGFRβ targeted activated HSCs in fibrotic liver. IgBD provided Z-IgBD-P16 with IgG binding and prolonged the circulatory half-life in blood. These two superiorities endowed Z-IgBD-P16 with the higher fibrotic liver uptake and stronger apoptosis-inducing activity in activated HSCs, resulting in the enhanced anti-liver fibrosis efficacy in vivo via the mitochondrial-dependent pathway. These findings suggest that Z-IgBD-P16 represents a promising targeted candidate for liver fibrosis treatment. Moreover, the application of dual strategies based on IgBD-mediated long-acting capacity and Z PDGFRβ -mediated targeting of PDGFRβ to design other functional peptide or protein can enhance the treatment efficacy of PDGFRβ-overexpressing other diseases.

Source: Pharmacological Research

DOI: 10.1016/j.phrs.2025.108010