HEBP2 (heme binding protein 2) is a multifunctional protein with emerging roles in cancer metabolism, mitotic regulation, and immune responses. Mechanistically, HEBP2 regulates glutamine metabolism in tumor cells by disrupting FOXA1 cytoplasmic phase separation and promoting nuclear translocation, thereby upregulating glutathione S-transferase P1 (GSTP1) expression 1. This metabolic activity creates a glutamine competition between tumor cells and tumor-associated macrophages, with HEBP2-high tumors exhibiting enhanced glutamine consumption that induces ferroptosis in CCL3+ macrophages and impairs antitumor immunity 1. HEBP2 also functions in mitotic spindle regulation through its interaction with ALG-2 (apoptosis-linked gene 2), where the deregulated ALG-2/HEBP2 axis alters microtubule dynamics and spindle orientation, promoting genomic instability in breast and lung cancer cells 2. Additionally, HEBP2 interacts with ALG-2 to modulate HIV-1 production by affecting Gag expression and distribution 3. Clinically, HEBP2 shows promise as a therapeutic target in triple-negative breast cancer, where GSTP1 inhibition combined with HEBP2 modulation sensitizes tumors to immunotherapy 1. HEBP2 has also been implicated in intervertebral disc degeneration through immune regulatory pathways 4 and insomnia susceptibility with reduced expression in affected brains 5.