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1 Introduction 1.1 Immune-metabolic dysregulation in metabolic diseases: an unmet therapeutic need Immune dysregulation underlies a broad range of human diseases, including metabolic disorders such as type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatohepatitis (MASH) ( + T cell exhaustion ( Reactive sulfur species (RSS), emerging as a distinct redox system beyond reactive oxygen species (ROS) and reactive nitrogen species (RNS), exhibit unique immunomodulatory properties ( The RSS family, comprising hydrogen sulfide (H 2 S), persulfides, polysulfides, and related sulfur-based modifications, exerts immunoregulatory functions primarily through protein persulfidation (S-Sulfhydration), a post-translational modification that alters protein conformation, activity, and interactions ( 2 S generation and downregulated expression of RSS-producing enzymes (cystathionine -synthase, CBS