A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsis

Xiangyu Wang, Zhaozheng Li, Yang Bai, Rui Zhang, Ran Meng, Fangping Chen, Haichao Wang, Timothy R. Billiar, Xianzhong Xiao, Ben Lu*, Yiting Tang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Caspase-11, a cytosolic lipopolysaccharide (LPS) receptor, mediates lethal immune responses and coagulopathy in sepsis, a leading cause of death worldwide with limited therapeutic options. We previously showed that over-activation of caspase-11 is driven by hepatocyte-released high mobility group box 1 (HMGB1), which delivers extracellular LPS into the cytosol of host cells during sepsis. Using a phenotypic screening strategy with recombinant HMGB1 and peritoneal macrophages, we discovered that FeTPPS, a small molecule selectively inhibits HMGB1-mediated caspase-11 activation. The physical interaction between FeTPPS and HMGB1 disrupts the HMGB1-LPS binding and decreases the capacity of HMGB1 to induce lysosomal rupture, leading to the diminished cytosolic delivery of LPS. Treatment of FeTPPS significantly attenuates HMGB1- and caspase-11-mediated immune responses, organ damage, and lethality in endotoxemia and bacterial sepsis. These findings shed light on the development of HMGB1-targeting therapeutics for lethal immune disorders and might open a new avenue to treat sepsis.

Original languageEnglish
Article number402
JournalCell Death and Disease
Issue number4
StatePublished - Apr 2021
Externally publishedYes


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