High Mobility Group Box 1 (HMGB1) in Cutaneous Inflammation: An Immune Modulator Bridging Cellular Stress, Ferroptosis and Danger Signaling

High mobility group box 1 (HMGB1) is a dynamic, multifunctional non-histone chromatin protein that translocates between the nucleus, cytoplasm, and extracellular space in response to various stressors. Beyond its nuclear role in chromatin organization and DNA repair, HMGB1 functions as a danger-associated molecular pattern (DAMP), orchestrating autophagy, inflammation, and immune responses through interactions with receptors such as Toll-like receptor 4 (TLR4), the receptor for advanced glycation end-products (RAGE), and CXCR4. This review summarizes HMGB1's structural features, posttranslational modifications (PTMs), and context-dependent signaling across subcellular compartments. Emphasis is placed on its involvement in dermatological conditions including psoriasis, atopic dermatitis, UVB-induced ferroptosis, pigmentation, and photoaging. We further discuss therapeutic modulation of HMGB1, including redox-sensitive interventions and secretiontargeted strategies. Natural compounds such as glycyrrhizin, epigallocatechin gallate (EGCG), and resveratrol demonstrate regulatory effects on HMGB1 activity, supporting their potential roles in skin health and cosmeceutical formulations. A comprehensive understanding of HMGB1’s spatial dynamics and regulatory mechanisms offers novel insights for managing inflammation, barrier dysfunction, and aging in dermatology.