Posttranslational Modifications of p62/SQSTM1 in Health and Disease

ABSTRACT p62/SQSTM1 is a multifunctional adaptor protein that serves as a central hub integrating cellular stress responses, including selective autophagy, antioxidant defense, metabolism, and immune signaling. Its diverse functions are precisely orchestrated by a complex network of posttranslational modifications (PTMs) that dynamically regulate its conformation, protein interactions, stability, and subcellular localization. This review provides a comprehensive overview of the p62 PTMs landscape, encompassing phosphorylation, ubiquitination, acetylation, methylation, and emerging cysteine‐based modifications. We first discuss how these PTMs coordinately maintain cellular homeostasis by fine‐tuning autophagic flux, activating antioxidant programs, coordinating nutrient sensing, preserving genomic stability, and regulating immune responses. We then examine how dysregulation of this PTMs network drives pathogenesis in major diseases including cancer, neurodegenerative disorders, metabolic diseases, and infections, with emphasis on context‐dependent molecular mechanisms. Furthermore, we summarize current preclinical evidence targeting p62 PTMs. Finally, we emphasize the critical need for advanced technologies to decipher PTMs crosstalk and dynamic regulation, coupled with the development of corresponding therapeutic strategies, to advance precision medicine. Understanding the p62 PTMs code offers promising opportunities for developing novel biomarkers and targeted therapies for human diseases.