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Using this platform, we identified hypermonol J (HPJ), a polycyclic polyprenylated acylphloroglucinol (PPAP), as a high\u2010affinity small\u2010molecule binder of tumor necrosis factor (TNF) (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>D<\/jats:sub>\n                    = 25.9\u00a0pM). SPR and orthogonal isothermal titration calorimetry (ITC) supported direct TNF binding, whereas mechanistic assays suggested that HPJ may preferentially stabilize TNF dimers, thereby impairing trimer assembly and downstream TNF receptor 1 (TNFR1)\/nuclear factor kappa B (NF\u2010\u03baB) signaling. In a preclinical psoriasis model, topical 1% HPJ alleviated imiquimod (IMQ)\u2010induced epidermal hyperplasia and suppressed IL\u201017\/IL\u201023 pathways. In an acute lung injury (ALI) model, 10\u00a0mg\/kg HPJ reduced neutrophil infiltration, lowered serum inflammatory cytokine levels, and restored pulmonary tight junction integrity. Biosafety assessments supported the preliminary tolerability of HPJ under the tested conditions. These findings identify HPJ as a promising small\u2010molecule lead for further pharmacological optimization and underscore the value of SPR\u2010guided natural product discovery for inflammatory storm intervention.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70960","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:02:16Z","timestamp":1787900536000},"source":"Crossref","is-referenced-by-count":1,"title":["SPR\u2010UPLC\u2010QTOF\/MS\u2010GNPS\u2010Guided Discovery of Hypermonol J as a Novel Tumor Necrosis Factor\u2010Binding Small\u2010Molecule Lead for Inflammatory Storm Intervention"],"prefix":"10.1002","volume":"7","author":[{"given":"Yongqi","family":"Li","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, and Wuhan (China\u2013Romania) Belt and Road Joint Laboratory on Traditional Chinese Medicine, School of Pharmacy, Tongji Medical College Huazhong University of 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