The editorial by Nobuhiro Nakamura provides an overview of the ubiquitin system and its significance in maintaining cellular homeostasis and controlling various cellular functions. The system's dysfunction is linked to numerous human diseases, particularly neurodegenerative disorders, making it a promising drug target. However, the complex nature of the ubiquitin system, involving a vast array of substrate proteins, ubiquitin ligases (E3s), and deubiquitinating enzymes (DUBs), poses significant challenges in understanding its physiological and pathophysiological actions. The special issue "Ubiquitin System" aims to enhance knowledge about the biochemical, structural, and pathophysiological aspects of the ubiquitin system. It includes 18 selected papers that cover various topics, such as the regulation of intracellular signaling pathways, the role of ubiquitination in cellular stress responses, and its involvement in autoimmune and inflammatory diseases. Specific examples include the regulation of TGF-β signaling, MAPK signaling, and GPCR signaling, as well as the impact of ubiquitination on mitochondrial function, cardiac contractility, and pulmonary fibrosis. The editorial also highlights the importance of non-canonical ubiquitination and the challenges in studying ubiquitination due to the difficulty in producing sufficient amounts of ubiquitinated proteins. Additionally, it discusses the therapeutic potential of ubiquitin system targeting in conditions like atherosclerosis and pulmonary fibrosis. Overall, the special issue provides valuable insights into the multifaceted roles of the ubiquitin system and its implications for both basic research and clinical applications.The editorial by Nobuhiro Nakamura provides an overview of the ubiquitin system and its significance in maintaining cellular homeostasis and controlling various cellular functions. The system's dysfunction is linked to numerous human diseases, particularly neurodegenerative disorders, making it a promising drug target. However, the complex nature of the ubiquitin system, involving a vast array of substrate proteins, ubiquitin ligases (E3s), and deubiquitinating enzymes (DUBs), poses significant challenges in understanding its physiological and pathophysiological actions. The special issue "Ubiquitin System" aims to enhance knowledge about the biochemical, structural, and pathophysiological aspects of the ubiquitin system. It includes 18 selected papers that cover various topics, such as the regulation of intracellular signaling pathways, the role of ubiquitination in cellular stress responses, and its involvement in autoimmune and inflammatory diseases. Specific examples include the regulation of TGF-β signaling, MAPK signaling, and GPCR signaling, as well as the impact of ubiquitination on mitochondrial function, cardiac contractility, and pulmonary fibrosis. The editorial also highlights the importance of non-canonical ubiquitination and the challenges in studying ubiquitination due to the difficulty in producing sufficient amounts of ubiquitinated proteins. Additionally, it discusses the therapeutic potential of ubiquitin system targeting in conditions like atherosclerosis and pulmonary fibrosis. Overall, the special issue provides valuable insights into the multifaceted roles of the ubiquitin system and its implications for both basic research and clinical applications.