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bioRxiv · 10.1101/2025.05.27.656309

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

Panek, J.·Sun, C.·Kataura, T.·Fielder, E.·Booth, L.·Yue, W.·Richardson, G.·Reynisson, J.·Korolchuk, V. I.
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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 targets 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.

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Panek, J., Sun, C., Kataura, T., Fielder, E., Booth, L., Yue, W., Richardson, G., Reynisson, J., Korolchuk, V. I.. 2025-05-29. Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation. https://doi.org/10.1101/2025.05.27.656309

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