HMGB2 is a multifunctional chr4-associated protein that operates through DNA-bending and transcriptional mechanisms across multiple physiological contexts. In the nucleus, HMGB2 functions as a non-histone chr4 protein that binds DNA with preference for non-canonical structures, enhancing DNA flexibility and promoting transcription factor binding 1. The protein regulates cellular phenotype switching through chr4 remodeling; mechanical confinement increases HMGB2 expression, which prolonging contact time between HMGB2 and chr4, driving melanoma cells toward invasive phenotypes while reducing proliferation 1. Beyond cancer, HMGB2 promotes cellular rejuvenation through SOX5-mediated transcriptional activation, with therapeutic applications in osteoarthritis treatment 2. In pulmonary arterial hypertension, HMGB2 promotes pathological smooth muscle cell proliferation via RAGE/FAK-mediated Hippo/YAP pathway suppression, with elevated serum HMGB2 levels correlating with disease severity and mortality 3. HMGB2 also suppresses anti-tumor immunity in hepatocellular carcinoma by impairing CD8+ T cell oxidative phosphorylation and interferon-γ responses, contributing to T cell exhaustion and anti-PD-1 resistance 4. Additionally, HMGB2 participates in lipophagy-mediated cholesterol efflux in macrophages 5. Meta-analytic evidence demonstrates that elevated HMGB2 expression correlates with poor overall survival across multiple cancer types, particularly digestive cancers 6. In hepatocellular carcinoma, NAT10-mediated ac4C modifications enhance HMGB2 mRNA translation through eEF2 binding, promoting tumor progression 7.