Xiaohui Wang, Xiaowei Lv, Honglv Jiang, Wenyun Zhu, Lindong Cao, Liang Zhou, Fang Chen Lin, Rong Deng, Li‐Fang Hu, Jingjing Ma, Jia-Bin Li, Guoqiang Xu
) restores the p62-mediated pathogenic autophagic degradation in primary cortical neurons and Huntington's disease mouse striatum. Mechanistically, p62 UFMylation enhances its interaction with LC3, augments autophagic flux, and eliminates pathogenic mutant huntingtin. Collectively, this work discovers a new post-translational modification, UFMylation, on p62 and establishes this modification as a key regulator of autophagy that promotes the clearance of mutant huntingtin, offering a potential target for therapeutic intervention.