Natural polycyclic aromatic naphthodianthrone compound S3273 calms cytokine storm to restore acute lung injury via...

CD39 participates in the process of ATP hydrolyzing into AMP, ADP and adenosine, and ATP mediates the channel-opening of P2X7 which further induces the downstream pyroptotic cell death. Current announced small-molecule CD39 enhancer are limited and to develop novel CD39 enhancer will be meaningful for inflammation-associated disorders treatment. CD39 enzymic screening assay was conducted to detect CD39 enhancing effect among a library of 424 FDA-approval small-molecule compounds. CETSA and SPR assay were arranged to assess the direct interaction between S3273 and CD39. Multiple techniques like YO-PRO-1 assay and patch clamp were employed to evaluate diverse CD39-P2X7 route modulators. RNA-Seq experiment was thereafter employed to fish potential targets in LPS-challenged mice. A polycyclic aromatic naphthodianthrone compound, S3273, was the most potent CD39 enhancer with EC₅₀ value of 5.66 μM. S3273 restored LPS-induced ALI via blocking NLRP3/GSDMD signaling to calm cytokine storm. In vitro, S3273 rescued pyroptosis via inhibiting the ROS accumulation, inflammasome assembly, as well as pyroptosis in a range types of macrophages. Mechanically, S3273 affected purinergic modulators including CD39, CD73, A2b and P2X7R to facilitate the formation and function of CD39-P2X7-dominated purinergic brake. IL-17 was a key pathway responsible for the protective effect of S3273 on LPS-induced ALI. S3273 directly binds to IL-17 and prevented the up-regulation of IL-17. S3273 calms cytokine storm to reverse lung damage in LPS-challenged mice, and these effects are at least partly through the modulation on CD39-P2X7R-IL-17A route.