Pharmacological researchSep 16, 2026

Changes in HMGB1 location over time affect organelle interactions and guide precise drug targeting in diabetic blood vessel disease

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 17, 2026

Abstract

Chronic stress in diabetes is linked to shifts in HMGB1 localization that may contribute to vascular complications.

HMGB1 can exist in three forms: nuclear, cytosolic, and extracellular, each with distinct functional roles.
Nuclear HMGB1 is involved in maintaining chromatin structure, while cytosolic HMGB1 is associated with stress response and autophagy.
Extracellular HMGB1 functions as a damage signal and is influenced by oxidative and metabolic stress conditions.
Changes in HMGB1 localization correlate with alterations in organelle interactions, particularly involving mitochondria and lysosomes.
In diabetic models, evidence suggests that HMGB1 is linked to lysosomal damage and extracellular signaling, although some mechanisms are context-dependent.
Understanding the spatial distribution of HMGB1 could inform targeted therapeutic strategies for diabetic vascular diseases.

Simplified

Diabetic vascular complications arise from persistent metabolic stress, chronic low-grade inflammation, and progressive loss of coordinated organelle homeostasis. HMGB1 is increasingly recognized as a context-dependent mediator linking metabolic stress with cellular responses, with its functions shaped by subcellular localization, redox state, and post-translational modification. Nuclear HMGB1 supports chromatin homeostasis, cytosolic HMGB1 participates in stress- and autophagy-related responses, and extracellular HMGB1 acts as a redox-sensitive damage-associated molecular pattern. Chronic glucotoxic, lipotoxic, oxidative, and endoplasmic reticulum stress are associated with shifts among these HMGB1 pools involving nuclear export, unconventional secretion, receptor-mediated signaling, and context-dependent re-entry. This spatiotemporal redistribution is linked to changes within the organelle interactome, including mitochondria-associated endoplasmic reticulum membranes (MAMs), mitochondrial quality control, endolysosomal homeostasis, and lipid-handling organelles, with reported associations across vascular, cardiac, retinal, renal, neurovascular, and platelet-neutrophil contexts. In diabetic models, the strongest available evidence currently concerns HMGB1-associated lysosomal injury and extracellular receptor signaling, whereas several MAM-, mitophagy-, and re-entry-related mechanisms remain context dependent. This spatial perspective may help define pharmacological strategies by distinguishing disease-associated extracellular or cytosolic HMGB1 pools from homeostatic nuclear HMGB1. Integrating HMGB1 localization, molecular state, organelle context, and cell type provides a spatial framework for developing more selective interventions in diabetic vascular disease.

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Changes in HMGB1 location over time affect organelle interactions and guide precise drug targeting in diabetic blood vessel disease

Abstract

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