Involvement of the pyroptosis-HMGB1 axis in systemic diseases

Pyroptosis is a lytic form of regulated cell death driven by inflammasome activation and gasdermin-mediated membrane rupture, characterized by robust inflammatory amplification. High-mobility group box 1 (HMGB1), a multifunctional nuclear protein and damage-associated molecular pattern, has emerged as a central regulator within pyroptosis-associated pathologies. Acting both as a downstream alarmin released during pyroptotic cell death and as an upstream licensing factor for inflammasome activation and innate immune signaling, HMGB1 establishes a context-dependent feedforward loop that shapes tissue injury and immune responses. In infectious and inflammatory disorders, excessive HMGB1 release exacerbates immune dysregulation and organ damage, whereas in selected tumor settings, pyroptosis-associated HMGB1 contributes to immunogenic cell death and antitumor immunity. This review systematically summarizes the molecular mechanisms underlying HMGB1-regulated pyroptosis, including canonical and noncanonical inflammasome pathways, gasdermin execution, and crosstalk with other regulated cell death programs. We further integrate evidence implicating the pyroptosis-HMGB1 axis across systemic diseases involving the nervous, respiratory, digestive, circulatory, urinary, locomotor, endocrine, reproductive, and immune systems. Finally, we discuss emerging therapeutic strategies targeting this axis, highlighting opportunities and challenges for disease-specific and precision interventions.