Molecular Mechanisms and Therapeutic Potentials of Triptolide in Autoimmune Diseases: Advances and Challenges.

The global incidence and prevalence of autoimmune diseases are increasing, and there is thus a need to develop novel, effective, and affordable therapeutic agents for autoimmune diseases. Triptolide (TP), a bioactive diterpenoid epoxide isolated from Tripterygium wilfordii Hook F, exhibits potent immunosuppressive and anti-inflammatory activities, and can be a potential therapeutic for multiple autoimmune diseases. The therapeutic effects of TP can be attributed to multiple mechanisms, including the inhibition of T cell and B cell activation, the restoration of T helper 17 cell/regulatory T cell balance, the suppression of pro-inflammatory cytokines, and the modulation of critical signaling pathways like the NF-κB, JAK/STAT, and PI3K/Akt pathways. TP alleviates pathological conditions by regulating oxidative stress responses and influencing gut microbiota composition. However, the clinical application of TP is limited due to severe dose-dependent and time-dependent toxic effects on the liver, kidneys, reproductive system, and other organs. Recent studies have highlighted several strategies, such as chemical structure modification, nanocarrier-based delivery systems, engineered exosomes, and combination pharmacotherapy, to both improve therapeutic efficacy and mitigate systemic toxicity. To provide insights for its safe clinical translation, this review systematically summarizes the pharmacological mechanisms, therapeutic potential, and toxicological challenges of TP in autoimmune diseases.