A Modular Peptide Strategy for Targeted Lysosomal Degradation of TGF-βR1.

Authors

Liang Qi, Daimin Luo, Wei Cheng, Qinglin Tang, Jiale Dong, Han Liu, Zhuowen Li, Yanqiu Yuan, Haonan Li, Xianxing Jiang

Published in

Journal of medicinal chemistry. Volume 69. Issue 21. Pages 25510-25531. Nov 12, 2026.

Abstract

Direct depletion of TGF-βR1 may provide more durable suppression of profibrotic signaling than occupancy-driven inhibition, but compact lysosome-directed degraders remain underdeveloped. Here, we report a peptide-based strategy for lysosomal degradation of TGF-βR1 by re-engineering a caveolin-derived antifibrotic scaffold. Structure-guided optimization identified T19 as an improved TGF-βR1-directed sequence, and incorporation of an intrinsic lysosome-targeting module generated P2, which induced time and dose-dependent, lysosome-dependent TGF-βR1 downregulation. Fatty-acid conjugation afforded P2-FA with improved stability and pharmacokinetic properties. P2-FA suppressed profibrotic signaling, reduced α-SMA and COL1A1 expression, and inhibited proliferation and migration of activated LX-2 cells. In a CCl4-induced mouse model, P2-FA attenuated collagen deposition, decreased fibrotic marker expression, and alleviated liver injury. These results identify P2-FA as a pharmacologically improved peptide-based TGF-βR1 degrader and antifibrotic lead.

PMID:
43018565
Bibliographic data and abstract were imported from PubMed on 12 Nov 2026.

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