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This study aimed to investigate the underlying therapeutic mechanism of the combination (CCSB) treatment in mice with ALI. A high dosage of lipopolysaccharide (LPS) was administered intraperitoneally to C57BL\/6 mice to establish an ALI model. The AMP\u2010Glo\u2122 assay was applied to screen for the component with the most potent CD39\u2010promoting enzyme activity from CCSB constituents migrating to the bloodstream. The PMA\u2010differentiated THP\u20101 and RAW264.7 macrophage cell lines were stimulated with LPS and adenosine triphosphate, followed by treatment with Jatrorrhizine (JH). The administration of CCSB demonstrated a notable improvement in lung injury through the modulation of the CD39\u2010P2X7 purinergic pathway and subsequent regulation of the NLRP3 inflammasome. The restrained CD39 and A2b were reversed by JH, leading to the suppression of the P2X7\u2010NLRP3 signaling pathway. In addition, the utilization of a CD39 inhibitor (POM\u20101) attenuated the inhibitory effect of JH on the NLRP3 signaling pathway. CCSB successfully rescued CSSLI, along with its small\u2010molecule component JH, which demonstrated the ability to inhibit the NLRP3 signaling pathway and pyroptosis, at least partially through regulating the CD39 enzyme.<\/jats:p>","DOI":"10.1002\/ptr.8062","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T14:09:20Z","timestamp":1744034960000},"page":"2374-2392","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Jatrorrhizine alleviates cytokine storm secondary lung injury via regulating <scp>CD39<\/scp>\u2010dominant purinergic braking and downstream <scp>NLRP3<\/scp> inflammasome"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7738-3328","authenticated-orcid":false,"given":"Yuejia","family":"Lan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese 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