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However, its upstream regulation remains poorly understood. Here, we identify Nemo\u2010like kinase (NLK) as a novel regulator of Caspase\u20108\u2013mediated PANoptotic signalling in sepsis. Integrated analyses of bulk (GSE65682) and single\u2010cell (GSE167363) transcriptomic datasets from patients with sepsis revealed elevated NLK expression in monocytes, strongly associated with PANoptotic effectors and adverse outcomes. Functional studies using NLK conditional knockout mice driven by Csf1r\u2010iCre and lipopolysaccharide\u2010stimulated bone\u2010marrow\u2010derived macrophages showed that NLK deficiency attenuated Caspase\u20108 cleavage, suppressed pyroptotic (cleaved Caspase\u20101, GSDMD\u2010N) and apoptotic (cleaved Caspase\u20103\/7) activation, and redirected cell\u2010death execution towards a necroptosis\u2010dominant program (p\u2010RIPK1\/3, p\u2010MLKL). This death\u2010mode redistribution was associated with attenuated cytokine release, reduced multiorgan injury, and improved survival. Mechanistically, NLK associated with the N\u2010terminal death effector domains (DEDs; amino acids 1\u2013216) of Caspase\u20108, thereby enhancing the efficiency of Caspase\u20108 recruitment and proximity\u2010induced activation within FADD\u2013RIPK1\/3\u2010containing PANoptosome complexes. NLK deletion impaired Caspase\u20108 activation within these complexes and promoted RIPK1\u2013RIPK3 necrosome assembly. Moreover, Caspase\u20108 overexpression in NKO macrophages partially restored GSDMD and Caspase\u20103 cleavage and reduced p\u2010MLKL, confirming that NLK is required for efficient Caspase\u20108 activation and optimal PANoptotic signalling. Collectively, these findings identify NLK as a regulatory rheostat of Caspase\u20108\u2013associated PANoptosis in sepsis and highlight the NLK\u2013Caspase\u20108 axis as a potential therapeutic target for fine\u2010tuning sepsis\u2010associated inflammatory cell death.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70616","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T06:40:48Z","timestamp":1770878448000},"source":"Crossref","is-referenced-by-count":6,"title":["NLK facilitates Caspase\u20108 activation to drive macrophage PANoptosis in sepsis"],"prefix":"10.1002","volume":"16","author":[{"given":"Yun","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Zhongnan Hospital of Wuhan University  Wuhan 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