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Although pyroptosis contributes to sepsis pathogenesis, the upstream receptors that trigger this process and constitute viable therapeutic targets remain elusive. Here, we identify C-X-C chemokine receptor type 4 (CXCR4) as a key upstream regulator of intestinal epithelial pyroptosis during septic injury. In a murine cecal ligation and puncture (CLP) model, sepsis robustly upregulated CXCR4 expression, which subsequently induced NLRP3 upregulation, caspase-1 activation, and generation of the gasdermin D N-terminal fragment (GSDMD-NT). Pharmacological inhibition of CXCR4 with the clinically approved antagonist AMD3100 (Plerixafor) significantly attenuated intestinal injury, restored the expression of tight junction proteins (ZO-1 and occludin), and suppressed pyroptotic markers. Conversely, CXCR4 agonism with NUCC-390 exacerbated intestinal damage. Mechanistically, CXCR4 activation enhanced NF-\u03baB p65 phosphorylation, thereby propelling NLRP3-dependent GSDMD cleavage. Genetic knockdown of GSDMD abolished NUCC-390-induced pyroptosis and barrier impairment without affecting NF-\u03baB activation, confirming GSDMD as the essential downstream executor. Furthermore, pharmacological inhibition of NF-\u03baB abrogated the exacerbation of intestinal injury, barrier dysfunction, and pyroptosis induced by CXCR4 activation, definitively establishing NF-\u03baB as a necessary signaling mediator within this CXCR4-driven pathway. These findings establish the CXCR4\/NF-\u03baB\/NLRP3\/GSDMD axis as a novel and therapeutically targetable pathway in septic intestinal injury. Importantly, we demonstrate that the FDA-approved CXCR4 antagonist AMD3100 represents a promising preclinical therapeutic candidate, exhibiting dual anti-inflammatory and anti-pyroptotic efficacy. Our work thus provides a mechanistically grounded rationale for further investigation of its repurposing potential in sepsis.<\/jats:p>","DOI":"10.1007\/s10753-026-02494-7","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:15:00Z","timestamp":1775121300000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological Targeting of CXCR4 Attenuates Sepsis-Induced Intestinal Injury by Suppressing NLRP3\/GSDMD-Mediated Pyroptosis"],"prefix":"10.1007","volume":"49","author":[{"given":"Hua","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingbin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"issue":"7\u20138","key":"2494_CR1","doi-asserted-by":"publisher","first-page":"16290","DOI":"10.20452\/pamw.16290","volume":"132","author":"S Oczkowski","year":"2022","unstructured":"Oczkowski, S., F. 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All methods are reported in accordance with ARRIVE guidelines for the reporting of animal experiments.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical Trial Number"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"140"}}