Exploring the Therapeutic Potential and Safety Profile of Tripterygium wilfordii Hook.f. in Osteoarthritis: Mechanisms, Toxicity, and Clinical Perspectives.

Abstract

Introduction: Tripterygium wilfordii Hook.f. (TwHF), A traditional Chinese medicine has been historically used for treating inflammatory conditions such as osteoarthritis (OA) and rheumatoid arthritis (RA), owing to its potent anti-inflammatory and immunomodulatory properties. Notably, OA is now recognized as a whole-joint disorder driven not merely by mechanical wear and tear, but by complex pathophysiological processes involving immune response dysregulation and localized metabolic disturbances. Despite its therapeutic potential, the clinical application of TwHF remains constrained by significant multi-organ toxicity and a narrow therapeutic window. This review aims to summarize the therapeutic mechanisms, toxicity profile, and clinical evidence of TwHF and its active components in OA treatment, and to discuss strategies for mitigating toxicity and future research directions.

Methods: A systematic search was performed across multiple electronic databases, including PubMed and Web of Science, up to February 2026, to identify studies on TwHF and its components in OA. The process followed PRISMA guidelines using keywords including "Tripterygium wilfordii," "osteoarthritis," and "toxicity." Included studies focused on TwHF and OA pharmacology, toxicity, or clinical outcomes; those with insufficient data were excluded. Data on authors, year, findings, and conclusions were extracted and synthesized narratively by themes.

Results: TwHF active components demonstrate potent anti-inflammatory and chondroprotective effects in cellular and animal OA models. However, they also cause dose-dependent hepatotoxicity, nephrotoxicity, and immunosuppression. Strategies like drug combination, targeted delivery, and metabolic modulation can reduce toxicity. Clinical evidence in OA remains limited and lowquality, whereas more robust data support its use in rheumatoid arthritis.

Discussion: TwHF presents a compelling therapeutic profile for OA due to its multi-faceted anti- inflammatory and immunomodulatory actions, primarily mediated by its active constituents through a multi-targeted approach. However, its promise is tempered by significant safety concerns, particularly hepatotoxicity and nephrotoxicity, and a lack of conclusive efficacy data from robust clinical trials in OA.Future research should prioritize high-quality RCTs, deeper investigation into toxicity mechanisms, development of safer derivatives, and establishment of predictive biomarkers.

Conclusion: While TwHF holds promise for OA treatment due to its multimodal anti-inflammatory mechanisms, its toxicity and insufficient clinical evidence necessitate further high-quality trials, precise therapeutic targeting, and safer formulation development for safe clinical integration.