2. Academic Validation
  3. Columbianadin targets TRIM7 to maintain P2X7 palmitoylation, inhibiting cuproptosis in synovial M2 macrophages

Columbianadin targets TRIM7 to maintain P2X7 palmitoylation, inhibiting cuproptosis in synovial M2 macrophages

  • Phytomedicine. 2025 Oct:146:157091. doi: 10.1016/j.phymed.2025.157091.
Zihao Li 1,  Ziyu Huang 2,  Xin Liao 3,  Hao Li 4
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital, Zhejiang University School of Medicine; Orthopedics Research Institute of Zhejiang University; Clinical Research Center of Motor System Disease of Zhejiang Province; Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City 310000, Zhejiang Province, PR China.
  • 2 Foreign Languages College, Shanghai Normal University, Shanghai City 200000, PR China.
  • 3 The Second Affiliated Hospital (Jiande Branch), Zhejiang University School of Medicine, Jiande City 311600, Zhejiang Province, PR China.
  • 4 The Second Affiliated Hospital, Zhejiang University School of Medicine; Orthopedics Research Institute of Zhejiang University; Clinical Research Center of Motor System Disease of Zhejiang Province; Zhejiang Key Laboratory of Motor System Disease Precision Research and Therapy, Hangzhou City 310000, Zhejiang Province, PR China. Electronic address: spinelihao@zju.edu.cn.
PMID: 40768810 DOI: 10.1016/j.phymed.2025.157091
Abstract

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.

Keywords

Columbianadin; Cuproptosis; Macrophage; Palmitoylation; Tripartite motif containing protein 7.

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