TN-derived P2-1 peptide inhibits HMGB1-pCTS-L axis, preventing RAGE engagement and macrophage pyroptosis.

Dysregulated inflammation, characterized by uncontrolled mediator release, is central to diseases like acute sepsis and chronic rheumatoid arthritis (RA). Current anti-inflammatory treatments often suffer from broad immunosuppression and partial efficacy, underscoring the need for targeted interventions. This review focuses on the pathogenic roles of High Mobility Group Box 1 (HMGB1) and procathepsin-L (pCTS-L), and their interactions with Toll-like receptor 4 (TLR4) and the Receptor for Advanced Glycation End Products (RAGE). A key gap is understanding and targeting the newly identified HMGB1-pCTS-L axis, which drives a sustained inflammatory loop.

This review synthesizes current understanding of the HMGB1-pCTS-L axis in dysregulated inflammation, identifying its role in sustained inflammatory loops and non-canonical NF-κB activation. It critically examines the pathogenic interactions of HMGB1 and pCTS-L with TLR4 and RAGE, highlighting how HMGB1 directly upregulates pCTS-L expression and release. The authors introduce the TN-derived P2-1 peptide as a novel, highly specific inhibitor designed to target this axis, detailing its proposed mechanism and therapeutic potential for sepsis and rheumatoid arthritis.

The review establishes the HMGB1-pCTS-L axis as a critical driver of dysregulated inflammation. It highlights that HMGB1 directly upregulates pCTS-L expression and release, initiating a delayed yet sustained inflammatory loop. This loop is proposed to predominantly activate the more enduring non-canonical NF-κB pathway, contributing to chronic inflammatory states. The intricate role of tetranectin (TN), an endogenous HMGB1-binding protein, is explored; it inhibits HMGB1 release but paradoxically facilitates HMGB1-induced pyroptosis. > The TN-derived P2-1 peptide is introduced 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. Furthermore, P2-1 specifically inhibits HMGB1-induced pCTS-L expression and release, demonstrating its ability to ameliorate both sepsis and rheumatoid arthritis even with delayed treatment. Its "disease-triggered" mechanism ensures selective targeting of extracellular HMGB1 only at pathological sites, promising enhanced safety and precision.