SQSTM1/p62 Post-Translational Modifications and Reverse Processes Modulate Disease Pathogenesis via KEAP1-NRF2 Signaling and Selective Autophagy

<b><i>Significance:</i></b> Sequestosome 1 (SQSTM1/p62, hereafter referred to as p62) is a multifunctional ubiquitin-binding autophagy receptor that acts as a critical bridge between the kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) pathway and selective autophagy through diverse post-translational modifications (PTMs) and their reverse processes. <b><i>Recent Advances:</i></b> As a selective autophagy receptor, p62 facilitates the degradation of ubiquitinated substrates while functioning as a signaling hub to orchestrate cellular responses to oxidative stress. Given its central role in multiple signaling pathways, p62 is subject to tight and intricate regulation. Beyond transcriptional control, p62 activity is finely modulated by diverse PTMs and their reverse processes, including phosphorylation, dephosphorylation, ubiquitination, deubiquitination, acetylation, deacetylation, S-Acylation, and deacylation, which collectively fine-tune its roles in selective autophagy and the KEAP1-NRF2 pathway. Mounting evidence underscores that the PTMs and their reverse processes of p62 are implicated in diverse pathologies through both direct and indirect mechanisms, spanning multiple cancer subtypes, neurodegenerative disorders, inflammatory conditions, non-alcoholic fatty liver disease (NAFLD), and metal-induced toxicity, as well as infectious diseases. <b><i>Critical Issues:</i></b> This review synthesizes current knowledge on the PTMs and their reverse processes of p62, its functional implications, its disease-associated mechanisms, and molecular regulators, aiming to provide novel insights for targeting the PTMs and their reverse processes of p62 in therapeutic strategies. <b><i>Future Directions:</i></b> Targeting p62 PTMs and their reverse processes may be a promising strategy to ameliorate various diseases, including cancer, neurodegenerative disorders, inflammatory conditions, NAFLD, metal-induced toxicity, and infectious diseases. <i>Antioxid. Redox Signal.</i> 43, 745-764.