- Ponatinib, identified from an 875-drug FDA-approved screen, inhibits NLRP3 inflammasome activation in bone marrow-derived macrophages without causing cytotoxicity.
- Effective non-cytotoxic concentrations determined: 1 μM for BMDMs and 0.5 μM for primary microglia, reducing IL-1β, IL-18 secretion and caspase-1 processing.
- Ponatinib reduces IL-1β secretion by microglia suggesting NLRP3 inhibition potential, but further testing required and cardiotoxicity risk warrants caution.
Immunobiology. 2026 Sep 4;231(5):153241. doi: 10.1016/j.imbio.2026.153241. Online ahead of print.
ABSTRACT
The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is an established driver of inflammation in diseases such as diabetes, Alzheimer’s disease, and gout. Previously, we screened 875 FDA-approved drugs for NLRP3 inhibitors and identified ponatinib as one of the five candidates that reduced NLRP3 inflammasome activation without causing cytotoxic effects in bone marrow-derived macrophages (BMDMs). Therefore, we hypothesize that ponatinib may be an effective NLRP3 inflammasome inhibitor. We performed dose curves and cytotoxicity assays to determine an effective in vitro concentration of ponatinib in BMDMs (1 μM) and primary microglia (0.5 μM) that reduced IL-1β secretion without inducing cytotoxicity. In BMDMs, ponatinib inhibited Nlrp3- and Caspase-1-dependent IL-1β and IL-18 secretion and significantly reduced caspase-1 processing. Ponatinib also reduced IL-1β secretion by microglia, indicating possible NLRP3 inflammasome inhibition in this cell type, but further testing is required. Although ponatinib has previously been demonstrated to drive cardiotoxicity-mediated inflammation, these data suggest that at specific doses, in vitro ponatinib can be non-cytotoxic and effective in attenuating NLRP3 inflammasome activation in macrophages and microglia.
PMID:42700769 | DOI:10.1016/j.imbio.2026.153241
Share Evidence Blueprint
Save to Google Notes
Search Google Scholar
Save as PDF
⭐ My Revision List
