Fibrillarin Resists Cellular Senescence Via SIRT1‐Dependent Nicotinamide Metabolism and Its Inhibition Sensitizes Senolytic Therapy in Esophageal Squamous Cell Carcinoma
8 affiliations
- 1Cancer Institute Longhua Hospital Shanghai University of Traditional Chinese Medicine Shanghai China
- 2Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation Shanghai China
- 3Department of Thoracic Surgery The Affiliated Tumor Hospital of Nantong University Nantong China
- 4Cancer Institute Affiliated Tumor Hospital of Nantong University Nantong China
- 5Department of Pathology The Affiliated Tumor Hospital of Nantong University Nantong China
- 6Department of Thoracic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
- 7Department of Medical Oncology Longhua Hospital Shanghai University of Traditional Chinese Medicine Shanghai China
- 8National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy for Medical Sciences and Peking Union Medical College Beijing China
Abstract
The importance of fibrillarin (FBL), an established nucleolar methyltransferase, was identified in neoplastic growth of esophageal squamous cell carcinoma (ESCC), one of the most lethal malignancies worldwide. However, the underlying mechanism remains unclear. Here, by enrolling independent ESCC cohorts, we verified the negative correlation between intratumoral FBL expression and patient prognosis. Notably, comprehensive transcriptomic and metabolomic analyses indicated that FBL deletion elicited cell cycle arrest and cellular senescence, as well as block of nicotinamide metabolism and increase of oxidative stress. Mechanistically, FBL could bind to and stabilize SIRT1 by obstructing the ubiquitin‐proteasome‐mediated protein degradation, therefore provoking nicotinamide metabolism, sustaining redox homeostasis, and counteracting senescence. Clinically, FBL‐SIRT1 axis was augmented in tumor tissues of ESCC patients, and high intratumoral SIRT1 expression predicted poor patient survival. Finally, we found that both genetic and pharmacological inhibition of FBL could sensitize senolytic therapy for ESCC. In conclusion, we first discovered FBL as an anti‐senescent protein in tumor progression. FBL resists cellular senescence by stabilizing SIRT1 and sustaining the nicotinamide metabolism, therefore providing an optional strategy for ESCC treatment by sensitizing senolytic therapy with FBL inhibitors.
Related
- Nicotinic acid starvation sensitizes nicotinate phosphoribosyltransferase-expressing tumors to nicotinamide phosphoribosyltransferase inhibition
- 1105 HER3 inhibition sensitizes metastatic colorectal and pancreatic cancer to immunotherapy
- Targeting MK2-Driven Stromal Senescence Sensitizes Breast Cancer Bone Metastasis to Immunotherapy
- Inhibition of the ATR-CHK1 signaling pathway sensitizes MCPyV-positive Merkel cell carcinoma to gemcitabine
- Targeting STAT5 abrogates survival signaling and sensitizes chronic lymphocytic leukemia cells to BCL-2 and MCL-1 inhibition
BibTeX
@article{jin2026fibrillarin,
title = {{Fibrillarin Resists Cellular Senescence Via SIRT1‐Dependent Nicotinamide Metabolism and Its Inhibition Sensitizes Senolytic Therapy in Esophageal Squamous Cell Carcinoma}},
author = {Xing Jin and Hong Liu and Ling Gao and Lei Liu and Ji‐Bin Liu and Xiaoxia Jin and Ming‐Song Wang and Dan Liu and Li Feng and Wen‐Lian Chen},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.76962},
url = {https://doi.org/10.1002/advs.76962},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Fibrillarin Resists Cellular Senescence Via SIRT1‐Dependent Nicotinamide Metabolism and Its Inhibition Sensitizes Senolytic Therapy in Esophageal Squamous Cell Carcinoma
AU - Xing Jin
AU - Hong Liu
AU - Ling Gao
AU - Lei Liu
AU - Ji‐Bin Liu
AU - Xiaoxia Jin
AU - Ming‐Song Wang
AU - Dan Liu
AU - Li Feng
AU - Wen‐Lian Chen
PY - 2026
DA - 2026/08/10
JO - Advanced Science
DO - 10.1002/advs.76962
UR - https://doi.org/10.1002/advs.76962
AB - The importance of fibrillarin (FBL), an established nucleolar methyltransferase, was identified in neoplastic growth of esophageal squamous cell carcinoma (ESCC), one of the most lethal malignancies worldwide. However, the underlying mechanism remains unclear. Here, by enrolling independent ESCC cohorts, we verified the negative correlation between intratumoral FBL expression and patient prognosis. Notably, comprehensive transcriptomic and metabolomic analyses indicated that FBL deletion elicited cell cycle arrest and cellular senescence, as well as block of nicotinamide metabolism and increase of oxidative stress. Mechanistically, FBL could bind to and stabilize SIRT1 by obstructing the ubiquitin‐proteasome‐mediated protein degradation, therefore provoking nicotinamide metabolism, sustaining redox homeostasis, and counteracting senescence. Clinically, FBL‐SIRT1 axis was augmented in tumor tissues of ESCC patients, and high intratumoral SIRT1 expression predicted poor patient survival. Finally, we found that both genetic and pharmacological inhibition of FBL could sensitize senolytic therapy for ESCC. In conclusion, we first discovered FBL as an anti‐senescent protein in tumor progression. FBL resists cellular senescence by stabilizing SIRT1 and sustaining the nicotinamide metabolism, therefore providing an optional strategy for ESCC treatment by sensitizing senolytic therapy with FBL inhibitors.
SN - 2198-3844
ER -