Spatiotemporal redistribution of HMGB1 shapes organelle interactome dysfunction and informs precision pharmacological targeting in diabetic vascular disease.

Abstract

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.