Pharmacological intervention of the HMGB1-pCTS-L axis to ameliorate inflammatory diseases

Dysregulated inflammation, characterized by the uncontrolled release of inflammatory mediators, is central to the pathogenesis of numerous inflammatory diseases, including acute sepsis and chronic rheumatoid arthritis (RA). Despite therapeutic advances in RA, limitations of current anti-inflammatory treatments-such as broad immunosuppression and partial efficacy-highlight an urgent need for novel interventions. This review critically examines the pathogenic roles of High Mobility Group Box 1 (HMGB1) and procathepsin-L (pCTS-L) in dysregulated inflammation, mediated by their interactions with Toll-like receptor 4 (TLR4) and the Receptor for Advanced Glycation End Products (RAGE). Crucially, we highlight the newly established HMGB1-pCTS-L axis, in which HMGB1 directly upregulates pCTS-L expression and release. This axis initiates a delayed yet sustained inflammatory loop, which may predominantly activate the more enduring non-canonical NF-κB pathway. Furthermore, we explore the intricate role of tetranectin (TN), an endogenous HMGB1-binding protein, which inhibits HMGB1 release but paradoxically facilitates HMGB1-induced pyroptosis. Leveraging this complexity, we introduce the TN-derived P2-1 peptide as a highly specific inhibitor of the HMGB1-pCTS-L axis. This peptide binds HMGB1 to prevent its RAGE engagement and subsequent macrophage pyroptosis, without broadly suppressing initial inflammatory cascades. It also specifically inhibits HMGB1-induced pCTS-L expression and release, ameliorating both sepsis and RA even with delayed treatment. Its "disease-triggered" mechanism, selectively targeting extracellular HMGB1 only at pathological sites, promises enhanced safety and precision. This review positions the HMGB1-pCTS-L axis as a critical and therapeutically tractable pathway, with HMGB1- and pCTS-L-inhibiting antibodies and mimetic peptides representing promising next-generation interventions for a spectrum of inflammatory diseases.