Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Columbianadin targets TRIM7 to maintain P2X7 palmitoylation, inhibiting cuproptosis in synovial M2 macrophages.
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Li Zihao, Huang Ziyu, Liao Xin, Li Hao
Аннотация
BACKGROUND: Traumatic synovitis often arises from sports injuries, and early intervention is crucial for preserving joint health. Columbianadin (CBN), a natural phytochemical, has demonstrated efficacy in inhibiting inflammatory progression through Chinese herbal injection therapy; however, its underlying mechanism remains unclear.
PURPOSE: This study aims to investigate the molecular mechanism by which CBN maintains P2X7 palmitoylation, characterize TRIM7 as a novel cuproptosis-alert protein, and provide a theoretical foundation for the bench-to-bedside translation of CBN in treating traumatic synovitis.
METHODS: A non-destructive anterior cruciate ligament tear model was established to induce knee joint instability in mice. TRIM7 conditional knockout mice were generated via tissue-specific gene knockout. Single-cell sequencing and bioinformatics analysis were used to screen and validate CBN targets and downstream signaling pathways. Subcellular localization changes of P2X7 were detected via fluorescence co-localization. Copper concentrations in cells and tissues were measured using inductively coupled plasma-mass spectrometry. Palmitoylation levels of P2X7 were analyzed via acyl-biotin exchange assay.
RESULTS: CBN effectively suppressed synovial inflammation in mice. Mechanistically, CBN directly bound to TRIM7 and downregulated its expression. TRIM7 knockout significantly attenuated CBN's anti-inflammatory effects. TRIM7 competed with P2X7 for binding to ZDHHC5, leading to ubiquitination-mediated degradation of ZDHHC5. This disrupted ZDHHC5-dependent palmitoylation of P2X7, preventing its membrane localization and subsequent copper efflux. Accumulated intracellular copper induced cuproptosis.
CONCLUSION: CBN directly targets TRIM7 to preserve ZDHHC5-mediated P2X7 palmitoylation, thereby inhibiting M2 macrophage cuproptosis in synovial tissues. These findings provide a theoretical basis for developing precision drug delivery systems targeting traumatic synovitis.
PURPOSE: This study aims to investigate the molecular mechanism by which CBN maintains P2X7 palmitoylation, characterize TRIM7 as a novel cuproptosis-alert protein, and provide a theoretical foundation for the bench-to-bedside translation of CBN in treating traumatic synovitis.
METHODS: A non-destructive anterior cruciate ligament tear model was established to induce knee joint instability in mice. TRIM7 conditional knockout mice were generated via tissue-specific gene knockout. Single-cell sequencing and bioinformatics analysis were used to screen and validate CBN targets and downstream signaling pathways. Subcellular localization changes of P2X7 were detected via fluorescence co-localization. Copper concentrations in cells and tissues were measured using inductively coupled plasma-mass spectrometry. Palmitoylation levels of P2X7 were analyzed via acyl-biotin exchange assay.
RESULTS: CBN effectively suppressed synovial inflammation in mice. Mechanistically, CBN directly bound to TRIM7 and downregulated its expression. TRIM7 knockout significantly attenuated CBN's anti-inflammatory effects. TRIM7 competed with P2X7 for binding to ZDHHC5, leading to ubiquitination-mediated degradation of ZDHHC5. This disrupted ZDHHC5-dependent palmitoylation of P2X7, preventing its membrane localization and subsequent copper efflux. Accumulated intracellular copper induced cuproptosis.
CONCLUSION: CBN directly targets TRIM7 to preserve ZDHHC5-mediated P2X7 palmitoylation, thereby inhibiting M2 macrophage cuproptosis in synovial tissues. These findings provide a theoretical basis for developing precision drug delivery systems targeting traumatic synovitis.