(M) Representative pictures of HE staining of livers. current agents used for treating SLE. Key words:Systemic lupus erythematosus, Triptolide, CD19, Antibodydrug conjugate, B cells, Reproductive toxicity, Synergistic effect, Targeted therapy == Graphical abstract == The antibodydrug conjugate (ADC) targeting CD19 loaded with TP has been constructed for clinical treatment of systemic lupus erythematosus (SLE) to alleviate TP’s toxicity and enhance of monoclonal antibody efficacy. == 1. Introduction == Tripterygium wilfordiiHook F (TWHF) is a widely used traditional Chinese medicinal plant whose extracts have been used as anti-inflammatory and immunosuppressive remedies for centuries1. More than 300 compounds have been identified from extracts of TWHF. Of these, many are diterpenoids, three of which dominate the chemical profile and the medicinal chemistry of TWHF, including triptolide (TP), tripdiolide, and triptonide2. TWHF exerts its anti-inflammatory and immunoregulatory activities mainly in two ways. On the one hand, the major diterpenoids of TWHF can suppress cytokine transcription and other proinflammatory genes by inhibiting related inflammatory signaling pathways, such as ERK1/2-NF-B and JAK/STAT signaling pathways3,4. On the other hand, the major diterpenoids of TWHF can regulate cell differentiation of immune cells or directly induce the death of immune cell death5,6,7. However, despite the impressive therapeutical effects on disease activity of autoimmune diseases and inflammatory disorders, side effects elicited by TWHF, including but not limited to hepatotoxicity, nephrotoxicity, and reproductive toxicity, are innegligible issues8,9,10. In addition, long-term administration of TWHF was reported to have decreased bone mineral density (BMD) levels in female patients with systemic lupus erythematosus (SLE), indicating that osteoporosis may be an essential problem for SLE patients treated with TWHF11. Unfortunately, the toxic ingredients of TWHF, especially TP, are just right in their medicinal composition, meaning that they cannot be eliminated in the clinical use of TWHF. Various delivery strategies Rabbit Polyclonal to LAMA3 have been designed to limit the adverse effects and enhance the efficacy of TP, but none have been successfully applied in clinical practice12,13. SLE is an autoimmune disease that affects multiple systems and organs and is more common in women of childbearing age aged 204014. It is estimated that the global prevalence of SLE is 43.7 per 100,000 people. Among women, the value is as high as 78.73 per 100,000 people15. The incidence rate is higher among Black, Asian, and Hispanic populations. SLE lesions involve the skin, skeletal system, respiratory system, cardiovascular system, etc. Renal failure and brain damage are common causes of death in SLE patients, having a mortality rate 23 times higher than the general human population16. At present, the medicines used in medical practice to treat SLE primarily include Fluoxymesterone antimalarial medicines, glucocorticoids, immunosuppressants, and monoclonal antibodies17. Long-term use of the antimalarial drug hydroxychloroquine poses a risk of retinal and corneal lesions. Long-term and large-dose use of glucocorticoids can cause secondary complications such as illness, hypertension, diabetes, osteoporosis, etc. Immunosuppressants such as cyclophosphamide can efficiently treat lupus nephritis. Still, there are Fluoxymesterone potentially severe side effects, including bone marrow suppression, illness, liver and kidney function damage, and gonadal suppression18. However, the immunological events that result in the onset of medical manifestations have not yet been fully defined. The central part of B cells in the pathogenesis of SLE offers more recently gained prominence19. Consequently, B cell-targeted Fluoxymesterone therapy has become probably one of the most promising.