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However, the absence of novel therapeutic targets constitutes a significant translational barrier, underscoring the urgent need for advancements in precision medicine. In this study, we demonstrate that the natural product luteolin (LU) effectively promotes LPS\u2010induced M1\u2010to\u2010M2 macrophage polarization by modulating the expression of pro\u2010inflammatory and anti\u2010inflammatory cytokines. Subsequently, thermal proteome profiling identifies receptor\u2010type protein tyrosine phosphatase \u03b1 (RPTP\u03b1) as a direct cellular target of LU in macrophages, which is validated by drug affinity responsive target stability, microscale thermophoresis, and surface plasmon resonance assays. Meanwhile, LU treatment inhibits RPTP\u03b1 phosphatase activity. Molecular docking suggests that LU interacts with the\n                    <jats:sup>405<\/jats:sup>\n                    PFTP\n                    <jats:sup>408<\/jats:sup>\n                    motif, impairing substrate recognition and subsequently suppressing the enzymatic activity of RPTP\u03b1. Furthermore, transcriptomic profiling reveals that LU significantly dysregulates 1,402 genes. Integrated kyoto encyclopedia of genes and genomes (KEGG) and gene set enrichment analysis demonstrate that LU suppresses the tumor necrosis factor (TNF) signaling pathways, which is reversed upon RPTP\u03b1 silencing. In vivo, LU exhibits potent anti\u2010inflammatory effects in both BALB\/c mice with sepsis\u2010induced ALI and CuSO\n                    <jats:sub>4<\/jats:sub>\n                    \u2010induced zebrafish inflammation models. Collectively, our study reveals that RPTP\u03b1 is a potential therapeutic target for modulating macrophage polarization. Moreover, LU may serve as a lead compound targeting RPTP\u03b1 for the treatment of sepsis\u2010induced ALI.\n                  <\/jats:p>","DOI":"10.1002\/cbic.70379","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:04:59Z","timestamp":1778569499000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Luteolin Ameliorates Sepsis\u2010Induced Acute Lung Injury by Targeting RPTP\u03b1 to Reprogram Macrophage M1\u2013M2 Polarization"],"prefix":"10.1002","volume":"27","author":[{"given":"Yang","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing China"},{"name":"Shihezi University College of Pharmacy Key Laboratory of Xinjiang Phytomedicine Resource and Utilization Shihezi University  Shihezi 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