Given the increasing hepatotoxicity risk associated with pyrrolizidine alkaloids (PAs) in Emilia sonchifolia (L.) DC., this study aimed to systematically characterize its PA components and identify the material basis responsible for liver injury. Using solid-phase extraction (SPE) enrichment coupled with ultra-high-performance liquid chromatography–quadrupole/orbitrap high-resolution mass spectrometry (UHPLC-HRMS), efficient annotation of PAs was achieved through building-block-based molecular network (BBMN) cluster analysis. A total of 76 PAs were identified (66 otonecine-type and 10 retronecine-type PAs), including 35 known compounds (e.g., senkirkine and petasitenine) and 41 potentially novel compounds. Semi-quantitative analysis revealed that senkirkine accounted for 86% of the total PAs. As an otonecine-type diester alkaloid, it serves as the core toxic substance triggering hepatic sinusoidal obstruction syndrome (HSOS). Network toxicology analysis identified 52 intersecting targets between senkirkine and hepatotoxicity. A protein–protein interaction (PPI) network was constructed, revealing 44 connected nodes with MAPK1, AKT1, and PIK3CA as key hub targets. Enrichment analysis indicated that these targets are primarily involved in the PI3K-Akt signaling pathway and focal adhesion. Molecular docking further validated that senkirkine exhibits strong binding affinities with these core targets, with binding energies ranging from −26.33 to −51.50 kcal/mol, stabilized by robust hydrogen-bonding networks. Consequently, senkirkine was identified as the critical safety indicator for quality control, and processing techniques were applied to reduce its content, balancing efficacy and toxicity risks.
Shan et al. (Fri,) studied this question.