HMGB3 is a high mobility group box protein that functions as a multifunctional chrX-associated protein involved in DNA repair, transcriptional regulation, and cellular stress responses. Structurally, HMGB3 contains an HMG Box A domain that enables DNA binding with preference for non-canonical structures and facilitates DNA bending to promote transcriptional activity 1. The protein plays critical roles in DNA damage repair, including stereospecific recognition and repair of minor-groove N2-alkyl-deoxyguanosine lesions 2. Functionally, HMGB3 serves as a transcriptional co-activator; it cooperatively enhances NANOG transactivation with SOX9 in prostate cancer, promoting oncogenic gene expression and cell migration 3. In small cell lung cancer, HMGB3 overexpression promotes cell migration through transcriptional regulation of cell junction genes 4. Dysregulation of HMGB3 is clinically significant across multiple malignancies. High HMGB3 expression predicts poor prognosis in gastric and breast cancers, with elevated expression correlating with aggressive clinicopathological features 56. In acute lung injury, HMGB3 upregulation contributes to inflammation and apoptosis through the circSLCO3A1/miR-424-5p/HMGB3 regulatory axis 7. HMGB3 overexpression is associated with immune infiltration and represents a potential diagnostic and therapeutic biomarker 8.