Senkyunolide I Inhibits mtDNA‐cGAS‐STING Signaling in Macrophages via Targeting VDAC1 Oligomerization to Attenuate Ulcerative Colitis
7 affiliations
- 1Center for Drug Research and Development Guangdong Pharmaceutical University Guangzhou Guangdong China
- 2Key Laboratory of Pathobiology Ministry of Education Jilin University Changchun Jilin China
- 3Department of Hepatobiliary‐Pancreatic & Hernia Surgery The Affiliated Guangdong Second Provincial General Hospital of Jinan University Guangzhou Guangdong China
- 4Department of Pharmacy Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University) Zhuhai China
- 5College of Pharmacy Guangdong Pharmaceutical University Guangzhou China
- 6School of Life Sciences Henan University Kaifeng Henan China
- 7Key Specialty of Clinical Pharmacy The First Affiliated Hospital of Guangdong Pharmaceutical University Guangzhou Guangdong China
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited therapeutic options. The cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway, activated by cytosolic mitochondrial DNA (mtDNA), has been increasingly implicated in UC. Through proteomics and artificial intelligence modeling, this study identified for the first time that senkyunolide I (SEI), a primary bioactive phthalide from Ligusticum striatum DC. (L. striatum), inhibits experimental colitis via the cGAS‐STING pathway, with mechanistic validation performed in both intestinal tissues and cultured macrophages. Mutagenesis, activity‐based protein profiling, and micro‐scale thermophoresis reveal that SEI directly binds voltage‐dependent anion channel 1 (VDAC1) at residue K12 to inhibit its stress‐induced oligomerization. This blockade prevents mtDNA release into the cytosol, thereby suppressing the cGAS‐STING cascade and subsequent M1 macrophage polarization, as well as downstream NLRP3 inflammasome activation, pyroptosis, and ferroptosis in macrophages and colon tissues. Overexpression of VDAC1‐WT and VDAC1‐K12A in mice confirms this mechanism. Clinically, VDAC1 expression in UC patients positively correlates with cGAS‐STING activation and disease severity. Collectively, SEI alleviates colitis by targeting VDAC1 oligomerization to inhibit the cGAS‐STING pathway in macrophages, establishing the VDAC1‐cGAS‐STING axis as a promising therapeutic strategy for UC.
Related
- Rhoifolin Alleviates Ulcerative Colitis by Targeting NMNAT1 and Activating SIRT1‐FOXO1 Signaling to Enhance ILC3s Effector Function
- Tumor immune cell targeting chimeras reprogram tumor-associated macrophages
- Precision targeting of tumor-associated macrophages via a 6-substituted pyrrolo[2,3-d]pyrimidine chimeric molecule for enhanced cancer immunotherapy
- Low-molecular-weight Ulva lacinulata extract exhibiting anti-inflammatory and pro-autophagic activities in RAW 264.7 macrophages: a promising candidate for the development of active ingredients targeting low-grade inflammation
- P2Y6 signaling selectively regulates TLR3-induced chemokine release in murine bone marrow-derived macrophages, with opposing effects on CCL2 and CXCL1
BibTeX
@article{ye2026senkyunolide,
title = {{Senkyunolide I Inhibits mtDNA‐cGAS‐STING Signaling in Macrophages via Targeting VDAC1 Oligomerization to Attenuate Ulcerative Colitis}},
author = {Zhiming Ye and Yihang Huang and Bohao Han and Lei Zhang and Can Yu and Yang Yang and Bing Liu and Yongping Jian and Zhixiang Xu and Cheng Zeng},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77045},
url = {https://doi.org/10.1002/advs.77045},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Senkyunolide I Inhibits mtDNA‐cGAS‐STING Signaling in Macrophages via Targeting VDAC1 Oligomerization to Attenuate Ulcerative Colitis
AU - Zhiming Ye
AU - Yihang Huang
AU - Bohao Han
AU - Lei Zhang
AU - Can Yu
AU - Yang Yang
AU - Bing Liu
AU - Yongping Jian
AU - Zhixiang Xu
AU - Cheng Zeng
PY - 2026
DA - 2026/08/07
JO - Advanced Science
DO - 10.1002/advs.77045
UR - https://doi.org/10.1002/advs.77045
AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited therapeutic options. The cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway, activated by cytosolic mitochondrial DNA (mtDNA), has been increasingly implicated in UC. Through proteomics and artificial intelligence modeling, this study identified for the first time that senkyunolide I (SEI), a primary bioactive phthalide from Ligusticum striatum DC. (L. striatum), inhibits experimental colitis via the cGAS‐STING pathway, with mechanistic validation performed in both intestinal tissues and cultured macrophages. Mutagenesis, activity‐based protein profiling, and micro‐scale thermophoresis reveal that SEI directly binds voltage‐dependent anion channel 1 (VDAC1) at residue K12 to inhibit its stress‐induced oligomerization. This blockade prevents mtDNA release into the cytosol, thereby suppressing the cGAS‐STING cascade and subsequent M1 macrophage polarization, as well as downstream NLRP3 inflammasome activation, pyroptosis, and ferroptosis in macrophages and colon tissues. Overexpression of VDAC1‐WT and VDAC1‐K12A in mice confirms this mechanism. Clinically, VDAC1 expression in UC patients positively correlates with cGAS‐STING activation and disease severity. Collectively, SEI alleviates colitis by targeting VDAC1 oligomerization to inhibit the cGAS‐STING pathway in macrophages, establishing the VDAC1‐cGAS‐STING axis as a promising therapeutic strategy for UC.
SN - 2198-3844
ER -