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Building on the clinical observation that Caspase-1 (CASP1) expression is elevated in AML and correlates with M2 macrophage abundance, we identify a novel signaling axis in AML cells, involving CASP1 and the transcription factor early growth response protein 4 (EGR4), that orchestrates macrophage polarization. Knockdown (KD) of CASP1 in human AML cells (THP-1, MOLM-13) shifted their secretome, which consequently skewed macrophage polarization away from the M2 phenotype at multiple levels. Mechanistically, transcriptomic sequencing revealed that CASP1 KD significantly upregulated EGR4 expression. Crucially, EGR4 interference partially reversed the macrophage-polarizing effects of CASP1 KD, establishing EGR4 as an essential downstream effector. In a xenograft model using NOD\/SCID mice\u2014a defined system for studying human AML-macrophage crosstalk\u2014CASP1 KD potently suppressed tumor growth. Immunohistochemical analysis revealed a remodeled microenvironment characterized by reduced proliferation (Ki67), upregulated EGR4, suppression of the M2-associated IL-10\/p-STAT3 pathway and CD206, alongside a concomitant increase in M1-associated marker CD86. In conclusion, our integrated analysis delineates a novel AML cell-intrinsic pathway wherein CASP1 represses EGR4, thereby enabling an M2-like macrophage phenotype via the IL-10\/p-STAT3 pathway. The identification of this CASP1-EGR4 axis identifies it as a promising therapeutic target for reshaping the immunosuppressive microenvironment in AML.<\/jats:p>","DOI":"10.1038\/s41598-026-41381-x","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T12:24:44Z","timestamp":1772195084000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Caspase-1-EGR4 axis regulates macrophage repolarization in acute myeloid leukemia cells"],"prefix":"10.1038","volume":"16","author":[{"given":"Yi","family":"Qian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zu-Xi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Feng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Hui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Hong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Xian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Juan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian-Sheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"issue":"4","key":"41381_CR1","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1172\/JCI129204","volume":"130","author":"L Vago","year":"2020","unstructured":"Vago, L. & Gojo, I. 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