**Background:** Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia due to impaired pancreatic β-cell function and insulin resistance, leading to complications such as diabetic cardiomyopathy (DCM), retinopathy (DR), nephropathy (DN), neuropathy, and foot disease. Autophagy, a conserved lysosomal degradation pathway, maintains cellular homeostasis by removing damaged organelles and misfolded proteins. High-mobility group box 1 (HMGB1) is a nuclear protein involved in DNA processes and acts as a damage-associated molecular pattern (DAMP) molecule. Both autophagy and HMGB1 are implicated in diabetes pathogenesis, but their interplay remains incompletely understood. This narrative review synthesizes current evidence on the relationship between HMGB1 and autophagy in diabetes and its complications, and discusses therapeutic strategies targeting these pathways.
**Methods:** The authors conducted a narrative review of recent literature, summarizing findings from experimental studies (in vitro and in vivo) and clinical observations. They searched for studies on HMGB1, autophagy, diabetes, and diabetic complications, focusing on molecular mechanisms and therapeutic interventions, particularly traditional Chinese medicine (TCM) compounds and formulas. The review includes data from animal models (e.g., STZ-induced diabetic rats, db/db mice) and cell lines (e.g., MIN6, HUVECs, podocytes).
**Key Results:** The review identifies a bidirectional regulatory loop between HMGB1 and autophagy. Intracellular HMGB1 can induce autophagy by binding to Beclin1, displacing Bcl-2, and activating the PI3K class III/Vps34 complex. Extracellular HMGB1 binds to RAGE and TLR4, activating signaling pathways (e.g., MAPK, NF-κB) that modulate autophagy. Conversely, autophagy regulates HMGB1 secretion: autophagy promotes HMGB1 translocation from nucleus to cytoplasm via ROS-dependent pathways and facilitates its extracellular release through HSP90AA1-mediated vesicular transport. In diabetes, hyperglycemia-induced oxidative stress upregulates HMGB1 and RAGE, leading to excessive autophagy and inflammation. Elevated serum HMGB1 correlates with HbA1c, fasting plasma glucose, HOMA-IR, and negatively with HOMA-β, indicating its role in insulin resistance and β-cell dysfunction. In DCM, HMGB1 mediates mitochondrial autophagy and myocardial injury; inhibiting HMGB1 reduces infarct size and improves cardiac function. In DR, HMGB1 contributes to lysosomal membrane permeabilization and autophagy inhibition, promoting inflammation and VEGF expression. In DN, HMGB1 activates Akt/mTOR signaling to inhibit autophagy, exacerbating podocyte injury. Several TCM compounds (e.g., glycyrrhizin, astilbin, dihydromyricetin, formononetin) and formulas (e.g., Jinkui Shenqi Decoction, Yiqi Tongluo Formula) modulate HMGB1 and autophagy to alleviate diabetic complications. Chemical drugs like SGLT2 inhibitors (e.g., dapagliflozin) and GLP-1 receptor agonists also regulate HMGB1 and autophagy.
**Clinical Implications:** The HMGB1-autophagy axis represents a promising therapeutic target for diabetes and its complications. Modulating HMGB1 levels or autophagy activity could mitigate inflammation, oxidative stress, and organ damage. TCMs offer a rich source of compounds that can either promote or inhibit autophagy depending on the context, providing potential adjunctive therapies. However, the exact mechanisms remain unclear, and further experimental and clinical studies are needed to validate these findings and develop targeted interventions.