Figure 7.

Schematic depicting HMGB1 deficiency-mediated nucleosome release linking chromosomal instability to the inflammatory response in K-Ras-driven PDAC. Oncogenic K-Ras^G12D leads to HMGB1 translocation and release into the extracellular space. Loss of intracellular HMGB1 increases chromosomal instability and promotes nucleosome release (current study). In addition, we previously demonstrated that extracellular nucleosome activates innate immune cells (e.g., macrophages) to secrete HMGB1 into circulation²⁴. Both extracellular nucleosome and HMGB1 exacerbates PDAC development by enhancing RAGE-dependent inflammatory responses.