Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction

@article{gao2026capsaicin,
  title = {{Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction}},
  author = {Xiaoning Gao and Wuyan Guo and Peiyuan Liu and Mingyue Yuwen and Hongyu Ren and Shengtao Hu and Zixiang Liu and Ruyang Tan and Kairui Liu and Zhiru Yang and Junli Ba and Xue Tao Bai and Shiti Shama and Cong Tang and Kai Miao and Haozhi Pei and Liren Liu and Cheng Zhu and Tao Wang and Bo Zhang and Jun Gu Kang},
  journal = {eLife},
  year = {2026},
  month = jun,
  doi = {10.7554/elife.97632.4},
  url = {https://doi.org/10.7554/elife.97632.4},
  note = {CC BY},
}

TY  - JOUR
TI  - Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction
AU  - Xiaoning Gao
AU  - Wuyan Guo
AU  - Peiyuan Liu
AU  - Mingyue Yuwen
AU  - Hongyu Ren
AU  - Shengtao Hu
AU  - Zixiang Liu
AU  - Ruyang Tan
AU  - Kairui Liu
AU  - Zhiru Yang
AU  - Junli Ba
AU  - Xue Tao Bai
AU  - Shiti Shama
AU  - Cong Tang
AU  - Kai Miao
AU  - Haozhi Pei
AU  - Liren Liu
AU  - Cheng Zhu
AU  - Tao Wang
AU  - Bo Zhang
AU  - Jun Gu Kang
PY  - 2026
DA  - 2026/06/09
JO  - eLife
DO  - 10.7554/elife.97632.4
UR  - https://doi.org/10.7554/elife.97632.4
AB  - Excessive alcohol consumption poses significant health risks and is closely associated with oxidative damage. The KEAP1-NRF2-ARE signaling pathway serves as the primary antioxidant system. However, current small molecule inhibitors are all covalently bound to KEAP1, meaning that once bound, they are not easily dissociated, while continuous inhibition of KEAP1 exhibits severe side effects. In this study, BLI, CETSA, Pull-down, Co-IP and HDX-MS assay analysis were conducted to detect the KEAP1 binding behavior of natural product, capsaicin (CAP), both in vitro and in cells. The ethanol-induced acute gastric mucosal damage rat model was also established to evaluate the therapeutic effect of CAP. Our findings demonstrated that CAP mitigated mitochondrial damage, facilitated the nuclear translocation of NRF2, leading to the up-regulation of downstream antioxidant response elements, HMOX1, TXN, GSS and NQO1 in GES-1 cells. Furthermore, CAP directly bind to KEAP1 and inhibit the interaction between KEAP1 and NRF2. In the KEAP1-knockout 293T cells, CAP failed to activate NRF2 expression. We identified that CAP non-covalently bound to Kelch domain and allosterically regulated three specific regions of KEAP1 : L342-L355, D394-G423 and N482-N495. To improve drug solubility and delivery efficiency, we developed IR-Dye800 modified albumin coated CAP nanoparticles. The nanoparticles significantly reduced the gastric mucosal inflammation and activated NRF2 downstream genes in vivo . Our hypothesis was further verified our hypothesis in Nfe2l2-knockout mice. This study provides new insights that CAP is a safe and novel NRF2 agonist by allosterically regulating KEAP1, which may contribute to the development of lead drugs for oxidative stress-related illness, e.g. aging, cancer, neurodegenerative and cardiovascular diseases.
SN  - 2050-084X
ER  -