Dehydrocorydaline treatment suppresses Th17 differentiation via the mTOR-mediated STAT3-RORγt signaling in systemic lupus erythematosus

Recent studies have demonstrated the pivotal role of pathogenic Th17 cells during the target organ damage in systemic lupus erythematosus (SLE). Therefore, identifying Th17-related precision therapeutic targets is essential for developing effective treatments. Potential targets of a novel alkaloid compound, Dehydrocorydaline (DHC), in SLE were investigated using integrated network pharmacology and molecular docking. The therapeutic efficacy of DHC was evaluated in vivo using a lupus-prone mouse model and in vitro via pathogenic Th17 polarization assays. Mechanistic studies were conducted using transcriptional analysis, cell thermal shift assay (CETSA), microscale thermophoresis (MST), and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR). This study demonstrates the therapeutic potential of DHC in SLE. Network pharmacology analysis identified mTOR signaling and Th17 cell polarization as key potential targets and pathways of DHC. In vivo, DHC treatment selectively reduced the frequencies of Th17 cells, inhibited serum IL-17A levels, restored glomerular filtration rate (GFR), and attenuated renal damage in lupus mice. Molecular docking, CETSA, and MST results suggested a direct interaction between DHC and mTOR. In vitro, DHC inhibited the phosphorylation of mTOR and STAT3 during pathogenic Th17 differentiation. Pharmacological activation of mTOR reversed the inhibitory effects of DHC on STAT3 activation and Th17 differentiation. Mechanistically, DHC blocked the mTOR-dependent STAT3 nuclear translocation and Rorc transcription during Th17 polarization. DHC attenuates renal damage in SLE by suppressing the Th17 response via the mTOR/STAT3/RORγt axis. This finding represents a novel therapeutic strategy for addressing the unmet clinical needs in SLE.