Supersulfides: A Promising Therapeutic Approach for Autoinflammatory Diseases.

Supersulfides are molecular species characterized by catenated sulfur moieties, including low-molecular-weight and protein-bound supersulfides. Emerging evidence suggests that these molecules, abundantly present in diverse organisms, play essential roles far beyond their chemical properties, such as functions in energy metabolism, protein stabilization, and antiviral defense. Recent studies highlight their regulatory effects on pattern-recognition receptors (PRRs) and associated signaling pathways-such as nucleotide oligomerization domain-like receptor signaling, toll-like receptor signaling, and type I interferon receptor signaling-critical for innate immunity and inflammatory responses. Dysregulation of these pathways is implicated in a heterogeneous group of autoinflammatory diseases, including inflammasomopathies, relopathies, and type I interferonopathies, respectively. Notably, both endogenous and synthetic supersulfide donors have recently shown promising inhibitory effects on PRR signaling, offering their potential as targeted therapies for managing autoinflammatory conditions. This review summarizes the fundamental biology of supersulfides and typical autoinflammatory diseases, focusing on their roles in innate immune and inflammatory responses, while exploring their therapeutic potential in these diseases.