SQSTM1/p62 at the Crossroads of Autophagy, Inflammation, and Lethal Infection

Sequestosome 1 (SQSTM1, also known as p62) has emerged as a multifunctional signaling adaptor that bridges autophagy, proteostasis, and inflammation. In this review, we discuss the molecular mechanisms by which SQSTM1 regulates selective autophagy and immune signaling pathways, and how its dynamic modulation shapes host responses during sepsis. We highlight the tissue-specific roles of SQSTM1 in sepsis-associated injury across major organs—including the liver, kidney, heart, lung, brain, and skeletal muscle—and explore its function as a damage-associated molecular pattern (DAMP) in the extracellular milieu. Recent studies implicate extracellular SQSTM1 in metabolic reprogramming and pro-inflammatory cytokine production via INSR signaling, supporting its classification as a novel DAMP and potential therapeutic target. We conclude a stage- and compartment-specific model for SQSTM1 during sepsis: its transition from a protective intracellular autophagy mediator in the early stage to a pathological extracellular DAMP in late stage. Furthermore, we discuss the translational relevance of pharmacological agents that modulate SQSTM1 levels or activity to restore immune balance and organ homeostasis. A better understanding of SQSTM1’s dual roles in immune activation and resolution could open new avenues for precision therapies in sepsis.