Multimodal AI‐Driven Identification of Dehydrocostus Lactone as a Potent Renal Fibrosis Attenuator Targeting IQGAP1

Renal fibrosis, a hallmark of chronic kidney disease (CKD), remains a critical therapeutic challenge with limited effective interventions. Herein, we proposed a multimodal AI-driven Traditional Chinese Medicine (TCM) symptom prediction model (TCM-SPred) and predicted potential herb-symptom associations between herbs and symptoms to obtain agents for treating renal fibrosis. The prediction results of TCM-SPred revealed that a natural guaianolide sesquiterpene lactone derivative dehydrocostus lactone (DCL, a main chemical constituent of Aucklandiae Radix) demonstrated significant anti-fibrotic effects in vivo (unilateral ureteral obstruction) and in vitro (TGF-β1-induced epithelial-mesenchymal transition). DCL directly targeted IQGAP1 to inhibit the Wnt signaling pathway by blocking the interaction between IQGAP1 and CCT3. These findings highlight the potential of DCL as a promising therapeutic candidate for renal fibrosis, providing novel insights into the IQGAP1-CCT3-Wnt signaling axis as a potential target for renal fibrosis intervention.