Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination.

Aspirin is a potent lysine acetylation inducer, but its impact on lysine ubiquitination and ubiquitination-directed protein degradation is unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile protein degradome in response to aspirin. By integrating degradome, acetylome, and ubiquitinome analyses, we show that aspirin impairs proteasome activity to inhibit proteasomal degradation, rather than directly suppressing lysine ubiquitination. Interestingly, aspirin increases lysosomal degradation-implicated K63-linked ubiquitination. Accordingly, using the major pathological protein of Parkinson's disease (PD), α-synuclein (α-syn), as an example of protein aggregates, we find that aspirin is able to reduce α-syn in cultured cells, neurons, and PD model mice with rescued locomotor ability. We further reveal that the α-syn aggregate clearance induced by aspirin is K63-ubiquitination dependent in both cells and PD mice. These findings suggest two complementary mechanisms by which aspirin regulates the degradation of soluble and insoluble proteins, providing insights into its diverse pharmacological effects that can aid in future drug development efforts.
Competing Interests: Competing interests: Y.Z., J.G. and K.H. have filed a patent application related to the use of aspirin or its derivatives for treating diseases associated with abnormal aggregation of α-syn. All other authors declare no competing interests. Ethics: All animal experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committee at the Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, and are in accordance with the Guide for the Care and Use of Laboratory Animals of the Chinese Academy of Sciences.
(© 2025. The Author(s).)