Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation.

Authors

Johan Panek, Edward Fielder, Congsing Sun, Steph Crabtree, Tetsushi Kataura, Niall Wilson, Lakshana Baheerathan, Jiangyu Tang, Laura Booth, Wyatt Yue, Gavin Richardson, Lauren Holder, Gavin J Miller, Jóhannes Reynisson, Sovan Sarkar, Viktor I Korolchuk

Published in

The Journal of biological chemistry. Pages 113430. Aug 10, 2026. Epub Aug 10, 2026.

Abstract

Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterise SQ-1, a small-molecule activator of autophagy that engages the prototypical SAR protein p62/SQSTM1 (sequestosome-1). We show that SQ-1 sensitises p62 to oxidation and promotes its disulphide-mediated oligomerisation in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 (NPC1) disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterised by defective autophagy.

PMID:
42575437
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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