Molecular engineering of lysosome-based degraders unveils a rapidly expanding therapeutic strategy
Abstract
The targeted degradation of oncogenic or misfolded proteins has emerged as a promising therapeutic strategy. While proteolysis-targeting chimeras (PROTACs) and related technologies have successfully hijacked the ubiquitin-proteasome system to eliminate disease-driving proteins, recent advances highlight the lysosome as a powerful alternative degradation route. Lysosome-based degradation strategies offer broader substrate scope, subcellular targeting flexibility, and the ability to degrade proteins beyond the reach of the proteasome. In this review, we provide a comprehensive overview of synthetic molecules and engineered systems designed to traffic target proteins to the lysosome. These include lysosome targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagy-tethering compounds (ATTECs), and other modalities that exploit endogenous trafficking pathways for selective protein clearance. By mapping the current landscape of lysosometargeting degraders, this article underscores the therapeutic potential of lysosomal proteolysis and outlines future directions for molecular engineering in this rapidly evolving field.
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BibTeX
@article{rivault2026molecular,
title = {{Molecular engineering of lysosome-based degraders unveils a rapidly expanding therapeutic strategy}},
author = {Adele Rivault and Jade Dussart-Gautheret and Rachid Benhida and Anthony R. Martin and Patrick Auberger and Arnaud Jacquel and Guillaume Robert},
journal = {Autophagy},
year = {2026},
month = oct,
doi = {10.1080/15548627.2026.2618626},
url = {https://hal.science/hal-05783954v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Molecular engineering of lysosome-based degraders unveils a rapidly expanding therapeutic strategy
AU - Adele Rivault
AU - Jade Dussart-Gautheret
AU - Rachid Benhida
AU - Anthony R. Martin
AU - Patrick Auberger
AU - Arnaud Jacquel
AU - Guillaume Robert
PY - 2026
DA - 2026/10/07
JO - Autophagy
DO - 10.1080/15548627.2026.2618626
UR - https://hal.science/hal-05783954v1
AB - The targeted degradation of oncogenic or misfolded proteins has emerged as a promising therapeutic strategy. While proteolysis-targeting chimeras (PROTACs) and related technologies have successfully hijacked the ubiquitin-proteasome system to eliminate disease-driving proteins, recent advances highlight the lysosome as a powerful alternative degradation route. Lysosome-based degradation strategies offer broader substrate scope, subcellular targeting flexibility, and the ability to degrade proteins beyond the reach of the proteasome. In this review, we provide a comprehensive overview of synthetic molecules and engineered systems designed to traffic target proteins to the lysosome. These include lysosome targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagy-tethering compounds (ATTECs), and other modalities that exploit endogenous trafficking pathways for selective protein clearance. By mapping the current landscape of lysosometargeting degraders, this article underscores the therapeutic potential of lysosomal proteolysis and outlines future directions for molecular engineering in this rapidly evolving field.
SN - 1554-8627
SN - 1554-8635
ER -