Processing with Cuscuta chinensis Lam. juice mitigates Tripterygium wilfordii Hook.F. toxicity via a multi-mechanistic approach and enhances its anti-rheumatic efficacy.

ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii Hook.F. (LGT) is a potent anti-rheumatic herb whose clinical utility is severely limited by multi-organ toxicity, particularly to the reproductive system. Detoxification strategies that preserve efficacy are urgently needed. Proper herb-juice excipient processing, a traditional Chinese medicine detoxification strategy, may mitigate toxicity while enhancing efficacy.

OBJECTIVE

This study aimed to evaluate whether processing LGT with the juice of Cuscuta chinensis Lam. (TSZ), a kidney-tonifying herb, could reduce toxicity and elucidate the underlying mechanisms.

MATERIALS AND

METHODS

The optimal processing protocol was determined by measuring triptolide (TP) content via HPLC. The detoxification effects of TSZ-processed LGT (TL) were assessed in mice after 90-day administration through histopathology and serum biomarkers. Mechanisms were investigated using network pharmacology prediction, Western blotting for G protein-coupled estrogen receptor (GPER), 16S rDNA sequencing for gut microbiota, and HPLC for component analysis. Anti-rheumatic efficacy was evaluated in a collagen-induced arthritis (CIA) model.

RESULTS

The results demonstrated that Processing with 20% TSZ juice maximally reduced TP content. TL significantly alleviated LGT-induced reproductive, hepatic, and renal toxicity, reversed testicular GPER overexpression, and restored gut microbiota dysbiosis (e.g., increased Ligilactobacillus). Three TSZ-derived flavonoids (hyperoside, astragalin, isoquercitrin) were introduced into TL. In the CIA model, medium-dose TL retained anti-rheumatic efficacy comparable to raw LGT, while high-dose TL exhibited superior efficacy, indicating a broadened therapeutic window.

CONCLUSION

In conclusion, TSZ juice processing effectively attenuates LGT toxicity, potentially mediated by a multi-mechanistic approach involving reduction of TP, introduction of protective flavonoids, modulation of gut microbiota, and regulation of testicular GPER. Crucially, this processing strategy broadens the therapeutic window of LGT, offering a promising approach for its safer clinical application.