Datta Sayantap, Rahman Mohammad Atiqur, Koka Saisudha, Boini Krishna M
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA.
Cells. 2024 Nov 23;13(23):1946. doi: 10.3390/cells13231946.
High Mobility Group Box 1 (HMGB1) is a highly conserved non-histone chromatin-associated protein across species, primarily recognized for its regulatory impact on vital cellular processes, like autophagy, cell survival, and apoptosis. HMGB1 exhibits dual functionality based on its localization: both as a non-histone protein in the nucleus and as an inducer of inflammatory cytokines upon extracellular release. Pathophysiological insights reveal that HMGB1 plays a significant role in the onset and progression of a vast array of diseases, viz., atherosclerosis, kidney damage, cancer, and neurodegeneration. However, a clear mechanistic understanding of HMGB1 release, translocation, and associated signaling cascades in mediating such physiological dysfunctions remains obscure. This review presents a detailed outline of HMGB1 structure-function relationship and its regulatory role in disease onset and progression from a signaling perspective. This review also presents an insight into the status of HMGB1 druggability, potential limitations in understanding HMGB1 pathophysiology, and future perspective of studies that can be undertaken to address the existing scientific gap. Based on existing paradigm of various studies, HMGB1 is a critical regulator of inflammatory cascades and drives the onset and progression of a broad spectrum of dysfunctions. Studies focusing on HMGB1 druggability have enabled the development of biologics with potential clinical benefits. However, deeper understanding of post-translational modifications, redox states, translocation mechanisms, and mitochondrial interactions can potentially enable the development of better courses of therapy against HMGB1-mediated physiological dysfunctions.
高迁移率族蛋白B1（HMGB1）是一种在物种间高度保守的非组蛋白染色质相关蛋白，主要因其对自噬、细胞存活和凋亡等重要细胞过程的调节作用而被认识。HMGB1根据其定位表现出双重功能：在细胞核中作为非组蛋白，在细胞外释放时作为炎症细胞因子的诱导剂。病理生理学研究表明，HMGB1在动脉粥样硬化、肾损伤、癌症和神经退行性变等多种疾病的发生和发展中起重要作用。然而，对HMGB1释放、易位以及介导此类生理功能障碍的相关信号级联反应的清晰机制理解仍不明确。本综述从信号传导的角度详细概述了HMGB1的结构-功能关系及其在疾病发生和发展中的调节作用。本综述还深入探讨了HMGB1的药物可及性现状、理解HMGB1病理生理学的潜在局限性以及为解决现有科学差距可开展的研究的未来前景。基于各种研究的现有范式，HMGB1是炎症级联反应的关键调节因子，驱动广泛功能障碍的发生和发展。专注于HMGB1药物可及性的研究已促成具有潜在临床益处的生物制剂的开发。然而，对翻译后修饰、氧化还原状态、易位机制和线粒体相互作用的更深入理解可能会推动针对HMGB1介导的生理功能障碍开发更好的治疗方案。
