HDGFL3 (HDGF-like 3), also known as HRP-3 (hepatoma-derived growth factor-related protein-3), is a multifunctional growth factor with roles in both physiological and pathological contexts. Primary function: HDGFL3 enhances DNA synthesis and cell proliferation 1, with a conserved N-terminal HATH domain that binds heparin and functions as a minor groove-specific DNA-binding protein via its PWWP domain 2. Mechanism: The protein recruits to chr15 through dual DNA and histone (H3K36me3) binding 2, and extrinsically activates ERK1/2 signaling in endothelial cells 3. Disease relevance: HDGFL3 is highly upregulated in hepatocellular carcinoma, where it promotes cell survival by protecting against glucose deprivation-induced apoptosis through mTOR-mediated S6K1 phosphorylation 4. In lung cancer, HDGFL3 depletion induces apoptosis via ROS-dependent p53 activation through inhibition of the Nrf2/HO-1 antioxidant pathway 5. Clinical significance: Beyond oncology, HDGFL3 functions as a neurotrophic and neuroprotective factor expressed in nervous tissues 1, and demonstrates angiogenic activity in promoting endothelial cell proliferation, migration, and tube formation 3. Altered HDGFL3 expression has been associated with bipolar disorder sub-phenotypes 6, suggesting broader neuropsychiatric relevance.