SQSTM1 is a therapeutic target for infection and sterile inflammation.

Inflammation represents a fundamental immune response triggered by various detrimental stimuli, such as infections, tissue damage, toxins, and foreign substances. Protein degradation plays a crucial role in regulating the inflammatory process at multiple levels. The identification of sequestosome 1 (SQSTM1, also known as p62) protein as a binding partner of lymphocyte-specific protein tyrosine kinase in 1995 marked a significant milestone. Subsequent investigations unveiled the activity of SQSTM1 to interact with diverse unstructured substrates, including proteins, organelles, and pathogens, facilitating their delivery to the lysosome for autophagic degradation. In addition to its well-established intracellular functions, emerging studies have reported the active secretion or passive release of SQSTM1 by immune or non-immune cells, orchestrating the inflammatory responses. These distinct characteristics render SQSTM1 a critical therapeutic target in numerous human diseases, including infectious diseases, rheumatoid arthritis, inflammatory bowel disease, pancreatitis, asthma, chronic obstructive pulmonary disease, and cardiovascular diseases. This review provides a comprehensive overview of the structure and modulation of SQSTM1, discusses its intracellular and extracellular roles in inflammation, and highlights its significance in inflammation-related diseases. Future investigations focusing on elucidating the precise localization, structure, post-translational modifications of SQSTM1, as well as the identification of additional interacting partners, hold promise for unravelling further insights into the multifaceted functions of SQSTM1.