Metabolomic Profiling and Network Toxicology: Mechanistic Insights into Effect of Gossypol Acetate Isomers in Uterine Fibroids and Liver Injury.

Objective: Gossypol is a natural polyphenolic dialdehyde product that is primarily isolated from cottonseed. It is a racemized mixture of (-)-gossypol and (+)-gossypol that has anti-infection, antimalarial, antiviral, antifertility, antitumor and antioxidant activities, among others. Gossypol optical isomers have been reported to differ in their biological activities and toxic effects.

Method: In this study, we performed a metabolomics analysis of rat serum using 1H-NMR technology to investigate gossypol optical isomers' mechanism of action on uterine fibroids. Network toxicology was used to explore the mechanism of the liver injury caused by gossypol optical isomers. SD rats were randomly divided into a normal control group; model control group; a drug-positive group (compound gossypol acetate tablets); high-, medium- and low-dose (-)-gossypol acetate groups; and high-, medium- and low-dose (+)-gossypol acetate groups.

Result: Serum metabolomics showed that gossypol optical isomers' pharmacodynamic effect on rats' uterine fibroids affected their lactic acid, cholesterol, leucine, alanine, glutamate, glutamine, arginine, proline, glucose, etc. According to network toxicology, the targets of the liver injury caused by gossypol optical isomers included HSP90AA1, SRC, MAPK1, AKT1, EGFR, BCL2, CASP3, etc. KEGG enrichment showed that the toxicity mechanism may be related to pathways active in cancer, such as the PPAR signaling pathway, glycolysis/glycolysis gluconeogenesis, Th17 cell differentiation, and 91 other closely related signaling pathways.

Conclusions: (-)-gossypol acetate and (+)-gossypol acetate play positive roles in the treatment and prevention of uterine fibroids. Gossypol optical isomers cause liver damage through multiple targets and pathways.