High-mobility group box 1 in acute kidney injury

Abstract

Acute kidney injury (AKI) remains a major clinical concern owing to its association with elevated morbidity and mortality. The nuclear protein high-mobility group box protein 1 (HMGB1), recognized for its evolutionary conservation, has emerged as a key mediator in AKI pathogenesis. Upon cellular injury, HMGB1 translocate into the extracellular space, where it operates as a damage-associated molecular patterns molecule. Its release intensifies inflammatory responses, exacerbates oxidative stress, and triggers ferroptosis. Furthermore, HMGB1 engages receptors such as TLRs and RAGE, ultimately contributing to various forms of regulated cell death. This review comprehensively summarizes the biological characteristics, regulatory mechanisms, and pathological roles of HMGB1 in AKI. It highlights HMGB1's central role in sepsis-associated AKI, ischemia-reperfusion injury, cisplatin-induced nephrotoxicity, and contrast-induced nephropathy. Moreover, HMGB1 demonstrates promising potential as a diagnostic and prognostic biomarker due to its early release and strong correlation with disease severity and outcomes. Targeting HMGB1 through natural compounds, small molecules, microRNAs, or specific antibodies shows therapeutic promise in preclinical models by attenuating inflammation, oxidative damage, and cell death. Future studies focusing on clinical validation and combination strategies may further establish HMGB1 as a diagnostic, prognostic, and therapeutic target, providing new avenues for improving AKI management and patient outcomes.

Keywords: HMGB1; TLR4; acute kidney injury; ferroptosis; inflammation; oxidative stress.

FIGURE 1

Molecular Structure and Functional Forms of HMGB1. Abbreviations: HMGB1, High-mobility group box protein 1; fr-HMGB1, Fully reduced HMGB1; ds-HMGB1, Disulfide HMGB1; ox-HMGB1, Fully oxidized HMGB1.

FIGURE 2

HMGB1 as a central mediator linking different injuries to AKI. (A) HMGB1 mediates ferroptosis and necroinflammation following ischemia-reperfusion, oxidative stress, and other AKI-inducing stimuli through interactions with ROS, MAPK, and autophagy pathways. (B) HMGB1 induces ER stress and inflammatory responses via TLR4, RAGE, and downstream effectors including PERK, CHOP, and NF-κB under various AKI-related insults. (C) HMGB1 promotes apoptosis, mitochondrial dysfunction, senescence, and pyroptosis in response to multiple pathological triggers such as sepsis, folic acid, contrast agents, and cisplatin. Abbreviations: AKI, Acute kidney injury; GPX4, Glutathione peroxidase 4; 4-HNE, 4-Hydroxynonenal; MDA, Malondialdehyde; PUFA, Polyunsaturated fatty acid; ACSL4, Acyl-CoA synthetase long-chain family member 4; ROS, Reactive oxygen species; JNK, c-Jun N-terminal kinase; ERK, Extracellular signal-regulated kinase; MAPK, Mitogen-activated protein kinase; HMGB1, High-mobility group box protein 1; CRM1, Chromosome region maintenance 1; RAGE, Receptor for advanced glycation end products; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3; NF-κB, Nuclear factor-kappa B; TNF-α, Tumor necrosis factor alpha; IL, Interleukin; TLR4, Toll-like receptor 4; MyD88, Myeloid differentiation primary response 88; MAL, MyD88-adapter-like protein; VCAM-1, Vascular cell adhesion molecule-1; ICAM-1, Intercellular adhesion molecule-1; IRAK4, Interleukin-1 receptor-associated kinase 4; LXA4, Lipoxin A4; PPAR-γ, Peroxisome proliferator-activated receptor-gamma; LIR, LC3-interacting region; SASP, Senescence-associated secretory phenotype; MMP3, Matrix metalloproteinase-3; MCP-1, Monocyte chemoattractant protein-1; CXCL1, C-X-C motif chemokine ligand 1; PINK1, PTEN-induced putative kinase 1; I/R, Ischemia/reperfusion; LPS, Lipopolysaccharide; AMPK, AMP-activated protein kinase; IRI, Ischemia-reperfusion injury; PERK, Protein kinase RNA-like ER kinase; IRE1α, Inositol-requiring enzyme 1 alpha; ATF, Activating transcription factor; CHOP, C/EBP homologous protein; sXBP1, Spliced X-box binding protein 1; MIP-2, Macrophage inflammatory protein-2; GRP78, Glucose-regulated protein 78; ER, Endoplasmic reticulum; p-eIF2α, Phosphorylated eukaryotic initiation factor 2 alpha.

FIGURE 3

Therapeutic mechanisms of drugs acting on HMGB1 in AKI. (A) Inhibitors of HMGB1–RAGE and HMGB1–TLR4 pathways, including lipoxin A4, esculetin, paclitaxel, and others, ameliorate sepsis-induced AKI by blocking inflammatory cascades. (B) HMGB1 inhibitors such as glycyrrhizic acid, ethyl pyruvate, and galantamine alleviate post-ischemic AKI through suppression of ROS, fibrosis, and inflammatory signaling. (C) Drugs including melatonin, liraglutide, folic acid, and glycyrrhizin attenuate cisplatin- and contrast-induced AKI by regulating HMGB1-mediated mitochondrial injury, oxidative stress, and apoptosis. (D) Targeting HMGB1–TLR2/RAGE signaling through agents like FGF2, PI3K/AKT agonists, and natural compounds reduces inflammation, apoptosis, and I/R-induced AKI. (E) Schematic summary of compounds that inhibit HMGB1 translocation, phosphorylation, receptor binding, or cytosolic activity, thereby suppressing HMGB1-driven AKI pathology. Abbreviations: AKI, Acute kidney injury; HMGB1, High-mobility group box protein 1; RAGE, Receptor for advanced glycation end products; PPAR-γ, Peroxisome proliferator-activated receptor-gamma; TLR4, Toll-like receptor 4; MyD88, Myeloid differentiation primary response 88; MAL, MyD88-adapter-like protein; NF-κB, Nuclear factor-kappa B; TNF-α, Tumor necrosis factor alpha; IL, Interleukin; FGF2, Fibroblast growth factor 2; FGFR, Fibroblast growth factor receptor; KATP, ATP-sensitive potassium channel; ROS, Reactive oxygen species; MMP, Matrix metalloproteinase; PI3K, Phosphatidylinositol-3-kinase; MAPK, Mitogen-activated protein kinase; CXCL1, C-X-C motif chemokine ligand 1; MCP-1, Monocyte chemoattractant protein-1; ICAM-1, Intercellular adhesion molecule-1; JAK2, Janus kinase 2; STAT3, Signal transducer and activator of transcription 3; a7 nAChR, Alpha-7 nicotinic acetylcholine receptor; SOCS3, Suppressor of cytokine signaling 3; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3.