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

ABSTRACT 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.