Molecular imaging-guided discovery of a potent natural FAPα inhibitor for liver fibrosis therapy.

Liver fibrosis can progress to cirrhosis and hepatocellular carcinoma, yet effective antifibrotic therapies remain limited. Fibroblast activation protein α (FAPα) is a promising biomarker and therapeutic target, but existing probes are constrained by limited tissue penetration and single-modality imaging, and effective FAPα-targeted antifibrotic agents remain lacking. Here we show that Cs-FAP, a hemicyanine-based near-infrared fluorescence/photoacoustic dual-modal probe, enables real-time and noninvasive visualization of FAPα activity in fibrotic liver tissue. Using a Cs-FAP-guided screening platform integrating high-content imaging and chromatographic purification, we screened 95 medicinal herbs and identified sappanchalcone (Sap) as a potent low-toxicity FAPα inhibitor. Sap markedly attenuated fibrosis progression and improved liver function in multiple liver fibrosis models using male mice. Mechanistically, Sap suppressed hepatic stellate cell activation through inhibition of the FAPα-PI3K-AKT signaling pathway. These findings establish Cs-FAP as a versatile platform for fibrosis imaging and drug discovery and identify Sap as a promising antifibrotic candidate.