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

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.