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In this study, through integrated approaches including high\u2010throughput virtual screening, target fishing technology, and atomic force microscopy (AFM) analysis, Forsythiaside E (FE) is first identified as a novel allosteric activator of pyruvate kinase M2 (PKM2) that promotes tetramer formation. Mutant protein construction combined with dynamic light scattering (DLS) and fluorescence resonance energy transfer (FRET) reveals FE binds to PKM2 K311 to promote tetramer formation. Employing Seahorse XF metabolic analyzers, real\u2010time single\u2010cell multi\u2010modal analysis systems, and transcriptome sequencing, it is revealed that FE\u2010mediated PKM2 tetramerization induces metabolic reprogramming in macrophages while suppressing STAT3 phosphorylation and subsequent NLRP3 transcriptional activation. In vivo assessments indicate that FE exhibited no significant multi\u2010organ toxicity. FE alleviates sepsis\u2010induced liver injury by promoting macrophage polarization toward the M2 anti\u2010inflammatory phenotype. Further validation through macrophage\u2010specific overexpression of PKM2 WT\/K311A in mice confirms FE's mechanism of action. Collectively, this study elucidates the molecular mechanism by which FE alleviates sepsis\u2010associated liver injury through targeted PKM2 tetramerization and proposes an innovative metabolic\u2010epigenetic coordinated regulation strategy for sepsis\u2010related liver injury treatment.<\/jats:p>","DOI":"10.1002\/advs.202514514","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T16:58:34Z","timestamp":1763139514000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Forsythoside E Alleviates Liver Injury by Targeting PKM2 Tetramerization to Promote Macrophage M2 Polarization"],"prefix":"10.1002","volume":"13","author":[{"given":"Bingxin","family":"Wu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome International Institute for Translational Chinese Medicine Guangzhou University of Chinese Medicine  Guangzhou Guangdong 510006 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