Rhoifolin Alleviates Ulcerative Colitis by Targeting NMNAT1 and Activating SIRT1‐FOXO1 Signaling to Enhance ILC3s Effector Function
4 affiliations
- 1Jiangsu Key Laboratory For Functional Substance of Chinese Medicine School of Pharmacy Nanjing University of Chinese Medicine Nanjing People's Republic of China
- 2Jiangsu Province Hospital of Chinese Medicine Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing People's Republic of China
- 3Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine Nanjing People's Republic of China
- 4College of Chemistry and Chemical Engineering Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education Hainan Normal University Haikou People's Republic of China
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disorder with limited therapeutic options, particularly those capable of selectively reinforcing intestinal epithelial barrier integrity while preserving immune homeostasis. Here, Rhoifolin (3, 10 mg/kg) dose‐dependently alleviates DSS and TNBS‐induced colitis in mice. Mechanistically, Rhoifolin selectively potentiates ILC3s effector function without affecting their proliferation, apoptosis, intestinal homing, developmental differentiation, or the distribution of CCR6+, NKp46+, and double‐negative ILC3s subsets. This functional enhancement promotes IL‐22 production, thereby reinforcing epithelial barrier integrity in colonic epithelial cells and organoids. Integrated transcriptomics and untargeted metabolomics identified nicotinamide salvage as a central metabolic program driving ILC3s functional enhancement. NMNAT1 was identified as a direct molecular target of Rhoifolin. Molecular docking and dynamic simulations pinpointed Leu155 as a critical residue mediating Rhoifolin‐NMNAT1 interaction, and mutation of Leu155 antagonized metabolic activation and IL‐22 induction. Consistently, Rhoifolin‐induced NAD+ elevation enhanced SIRT1 activity, leading to FOXO1 deacetylation and nuclear translocation. Further CUT&Tag‐qPCR demonstrated FOXO1 enrichment at Il22 promoter, driving IL‐22 transcription in ILC3s. Collectively, our findings identify Rhoifolin as a potent ILC3s effector function enhancer and uncover a previously unrecognized NMNAT1‐NAD+‐SIRT1‐FOXO1 axis linking immunometabolic and epigenetic regulation to intestinal barrier protection, highlighting ILC3s empowerment as a promising therapeutic strategy for UC.
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BibTeX
@article{yang2026rhoifolin,
title = {{Rhoifolin Alleviates Ulcerative Colitis by Targeting NMNAT1 and Activating SIRT1‐FOXO1 Signaling to Enhance ILC3s Effector Function}},
author = {Hongqiong Yang and Yishu Zhang and Sijia Feng and Xiaoqing Ma and Jiayi Feng and Junwei Wang and Jialin Gao and An Pan and Dapeng Wu and Kang Ding and Caijuan Zheng and Qi Lv and Lihong Hu},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.76935},
url = {https://doi.org/10.1002/advs.76935},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Rhoifolin Alleviates Ulcerative Colitis by Targeting NMNAT1 and Activating SIRT1‐FOXO1 Signaling to Enhance ILC3s Effector Function
AU - Hongqiong Yang
AU - Yishu Zhang
AU - Sijia Feng
AU - Xiaoqing Ma
AU - Jiayi Feng
AU - Junwei Wang
AU - Jialin Gao
AU - An Pan
AU - Dapeng Wu
AU - Kang Ding
AU - Caijuan Zheng
AU - Qi Lv
AU - Lihong Hu
PY - 2026
DA - 2026/08/07
JO - Advanced Science
DO - 10.1002/advs.76935
UR - https://doi.org/10.1002/advs.76935
AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disorder with limited therapeutic options, particularly those capable of selectively reinforcing intestinal epithelial barrier integrity while preserving immune homeostasis. Here, Rhoifolin (3, 10 mg/kg) dose‐dependently alleviates DSS and TNBS‐induced colitis in mice. Mechanistically, Rhoifolin selectively potentiates ILC3s effector function without affecting their proliferation, apoptosis, intestinal homing, developmental differentiation, or the distribution of CCR6+, NKp46+, and double‐negative ILC3s subsets. This functional enhancement promotes IL‐22 production, thereby reinforcing epithelial barrier integrity in colonic epithelial cells and organoids. Integrated transcriptomics and untargeted metabolomics identified nicotinamide salvage as a central metabolic program driving ILC3s functional enhancement. NMNAT1 was identified as a direct molecular target of Rhoifolin. Molecular docking and dynamic simulations pinpointed Leu155 as a critical residue mediating Rhoifolin‐NMNAT1 interaction, and mutation of Leu155 antagonized metabolic activation and IL‐22 induction. Consistently, Rhoifolin‐induced NAD+ elevation enhanced SIRT1 activity, leading to FOXO1 deacetylation and nuclear translocation. Further CUT&Tag‐qPCR demonstrated FOXO1 enrichment at Il22 promoter, driving IL‐22 transcription in ILC3s. Collectively, our findings identify Rhoifolin as a potent ILC3s effector function enhancer and uncover a previously unrecognized NMNAT1‐NAD+‐SIRT1‐FOXO1 axis linking immunometabolic and epigenetic regulation to intestinal barrier protection, highlighting ILC3s empowerment as a promising therapeutic strategy for UC.
SN - 2198-3844
ER -