2. Academic Validation
  3. Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis

Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis

  • Pharmacol Res. 2024 Mar 2:202:107128. doi: 10.1016/j.phrs.2024.107128.
Jiahui Ni 1,  Lijie Zhang 2,  Guize Feng 1,  Weilian Bao 1,  Yirui Wang 3,  Yuran Huang 1,  Tongqing Chen 1,  Jieli Chen 1,  Xinyue Cao 1,  Keyuan You 1,  Sheng Tan 1,  Thomas Efferth 4,  Hong Li 1,  Bo Li 5,  Xiaoyan Shen 6,  Yan You 7
Affiliations

Affiliations

  • 1 Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
  • 2 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 3 Artificial Intelligence Innovation and Incubation (AI³) Institute, Fudan University, Shanghai, China.
  • 4 Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany.
  • 5 Amway (Shanghai) Innovation & Science Center, 720 Cailun Road, Shanghai, China. Electronic address: robert.li@Amway.com.
  • 6 Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China; Shanghai Fifth People's Hospital, Fudan University, Shanghai, China; Artificial Intelligence Innovation and Incubation (AI³) Institute, Fudan University, Shanghai, China. Electronic address: shxiaoy@fudan.edu.cn.
  • 7 Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China. Electronic address: yyou@fudan.edu.cn.
PMID: 38438089 DOI: 10.1016/j.phrs.2024.107128
Abstract

The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of Ferroptosis. By the CETSA assay and DARTS assay, we identified Carbonic Anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on Ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by Ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of Ferroptosis, providing a promising therapeutic candidate for UC.

Keywords

CA9(CAIX); Ferroptosis; INSIG2; UC; Vanillic acid.

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