AI-Guided Structure-Aware Modeling and Thermal Proteomics Reveal Direct Demethylzeylasteral-ACLY Interaction

Demethylzeylasteral is identified as a direct interactor of ACLY from a screen of 50 structurally diverse natural products using thermal proteomics plus HoloGNN.

• Why it matters: Direct molecular targets of natural products are hard to pinpoint, limiting mechanistic understanding and therapeutic development.
• What they did: The team combined matrix-augmented thermal proteomics with HoloGNN, benchmarking on PDBbind datasets, then tested 50 natural products and validated hits with orthogonal biochemical assays.
• The result: Demethylzeylasteral shows micromolar binding and enzymatic inhibition of ACLY, reduces imiquimod-induced psoriasis-like severity in mice, and reverses keratinocyte hyperproliferation and ACLY-linked lipid metabolic reprogramming.

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