HMGB1 and HMGB2 proteins in ferroptosis, cancer, and neurodegeneration

Introduction High mobility group box (HMGB) proteins are nuclear DNA-binding factors that, once released from the nucleus, behave as damage-associated molecular patterns (DAMPs) capable of activating pattern recognition receptors (PRRs). The role of HMGB1 in cell death has been characterized in considerable detail, whereas HMGB2 has only lately been linked to immunogenic cell death (ICD) and ferroptosis. Clarifying how these closely related proteins differentially control oxidative forms of cell death has important implications for both cancer and neurodegenerative disease. Methods In this review, we have assembled recent mechanistic, cellular, and translational data on HMGB1 and HMGB2, with particular emphasis on studies that delineate their structural features, XPO1-dependent nuclear export, and downstream signaling networks in ferroptosis, cancer immunogenicity, and neurodegeneration. We highlight (in particular) quantitative proteomic, genetic, and pharmacologic experiments that differentiate HMGB1- from HMGB2-driven functions. Conclusion HMGB1 and HMGB2 occupy distinct yet complementary, positions at the crossroads of oxidative stress, ferroptosis, and inflammatory signaling. Signaling events that depend on nuclear export of these proteins govern chemotherapy-induced immunogenic cell death in cancer as well as contributing to chronic neuroinflammation and neuronal loss. Targeting HMGB-centered pathways, including XPO1-mediated export, with novel therapeutic strategies may therefore open new avenues for cancer immunotherapy and for neuroprotective interventions.