Investigating Podophyllotoxin-Induced Cardiotoxicity in Rats by Toxicological Evidence Chain (TEC): Focus on the Akt1/Srebp-1c/PUFAs Axis

Chuanxin Liu; Jiao Kong; Yali Lai; Yongchun Zhang; Ying Li; Jiangnan Du; Lu Sun; Yue Tian

doi:10.1016/j.cbi.2025.111634

Investigating Podophyllotoxin-Induced Cardiotoxicity in Rats by Toxicological Evidence Chain (TEC): Focus on the Akt1/Srebp-1c/PUFAs Axis

Chem Biol Interact. 2025 Jul 9:111634. doi: 10.1016/j.cbi.2025.111634. Online ahead of print.

Authors

Chuanxin Liu¹, Jiao Kong², Yali Lai³, Yongchun Zhang³, Ying Li¹, Jiangnan Du³, Lu Sun⁴, Yue Tian⁵

Affiliations

¹ Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Key Laboratory of Hereditary Rare Diseases of Health Commission of Henan Province, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003.
² Laboratory of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China, 310058.
³ School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing , China, 102488.
⁴ College of Chinese Materia Medica and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, China, 030619. Electronic address: sunlu_2013@163.com.
⁵ Drug/Medical Device Clinical Trial Institution, Ganzhou Key Laboratory of Clinical Drug Research, Center for Genetic Development and Regenerative Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China, 341000. Electronic address: tyyz0823@163.com.

PMID: 40645425
DOI: 10.1016/j.cbi.2025.111634

Abstract

Podophyllotoxin, an efficacious constituent derived from the traditional Chinese medicine Dysosma versipellis, exhibits antitumor properties; however, its toxicity limits clinical application. This study, based on the Toxicological Evidence Chain (TEC), employs metabolomics and lipidomics approaches to investigate the mechanisms underlying its cardiotoxicity. Injury phenotype evidence (IPE) was obtained through observation of the rats' external phenotypes, including coat condition, body weight, fecal characteristics, mental status, and presence of bleeding. Cardiac enzyme levels, blood lipid profiles, and histopathological examinations of heart tissues were assessed as evidence of adverse outcomes (AOE). To obtain evidence of toxic events, an integrated analysis of metabolomics, lipidomics, network toxicology was conducted on rat serum and heart tissues and molecular biology experiments in vitro, revealing the mechanism of PPT-induced cardiotoxicity. The results indicated that PPT induced pathological changes in rats, including weight loss, dull and brittle fur, and lethargy, along with nasal bleeding and diarrhea. The levels of AST, TC, and LDL-C were significantly elevated, while TG and HDL-C showed significant decreases. Integrated metabolomics analysis revealed 21 significantly altered differential metabolites demonstrating concordant directional changes across both serum and cardiac tissues. Complementary lipidomics profiling identified 31 dysregulated lipid species with coordinated variations in both biological matrices. These perturbed metabolites were principally associated with the core metabolic pathways: synthesis and metabolism of unsaturated fatty acid lipids. Network toxicology predictions identified Akt1, Egfr, Mtor, and Nos3 as potential critical molecular targets of PPT. In vitro experiments show that targeting the Akt1/Rebp-1c axis with PPT induces oxidative stress and cell death in cardiomyocytes, which can be mitigated by unsaturated fatty acids. This discovery offers a new approach for using PPT in clinical settings, potentially reducing its cardiotoxicity by administering unsaturated fatty acid simultaneously.

Keywords: Cardiotoxicity; Grades of Toxicological Evidence Assessment (GTEA); Lipidomic; Network toxicology; Podophyllotoxin; Toxicological evidence chain (TEC).