Rakez Kayed, PhD, The University of Texas Medical Branch, Galveston, TX, shares his thoughts on the potential of anti-high mobility group box 1 (HMGB1) agents for the treatment of neurodegenerative diseases. HMGB1 is a nonhistone chromatin-associated protein, which interacts with several binding partners to mediate transcriptional regulation, proliferation, differentiation, and senescence. It is also acts as a danger associated molecular pattern (DAMP) molecule that amplifies immune responses and functions as an extracellular inflammatory cytokine. New findings have demonstrated the role of tau oligomers in promoting cellular senescence via HMGB1, which could represent an important pathological mechanism in human tauopathies. Therefore, HMGB1-targeting molecules are of great therapeutic interest. Ethyl pyruvate (EP) and glycyrrhizic acid (GZA) are known inhibitors of HMGB1 release and were shown in this investigation to prevent the tau oligomer-induced senescence like phenotype in mouse models, ameliorating cognitive decline and tau pathology. Further research efforts should aim to identify new molecules targeting HMGB1 or its endogenous regulators. This interview took place at the Alzheimer’s Association International Conference (AAIC) 2022 in San Diego, CA.