CRAT-mediated acetylcarnitine shuttling sustains p65 acetylation and NF-κB-associated radioresistance in colorectal cancer.
5 affiliations
- 1Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, NHC Key Laboratory ofCancer and Metabolism (Fujian Cancer Hospital), Fuzhou, 350014, China.
- 2Department of Oncology, Chengdu Integrated TCM&Western Medicine Hospital, Affiliated Hospital of Integrative Chinese Medicine and Western Medicine of Chengdu University of TCM, Chengdu, 610095, China.
- 3Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, NHC Key Laboratory ofCancer and Metabolism (Fujian Cancer Hospital), Fuzhou, 350014, China. [email protected].
- 4Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, NHC Key Laboratory ofCancer and Metabolism (Fujian Cancer Hospital), Fuzhou, 350014, China. [email protected].
- 5Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, NHC Key Laboratory ofCancer and Metabolism (Fujian Cancer Hospital), Fuzhou, 350014, China. [email protected].
Abstract
Background
Neoadjuvant chemoradiotherapy is a standard treatment for locally advanced rectal cancer, yet acquired resistance limits durable tumor control. Whether stress-adaptive acetyl-group metabolism contributes to this resistance remains unclear.Methods
We performed a genome-wide CRISPR-Cas9 loss-of-function screen under fractionated irradiation and integrated the results with transcriptomic and proteomic profiling of radioresistant colorectal cancer models established by stepwise irradiation. CRAT function was interrogated using genetic perturbation, catalytic-dead reconstitution, acetylation-mimetic p65 rescue, RELA depletion, stable-isotope tracing, free coenzyme A quantification, NF-κB reporter assays, chromatin immunoprecipitation-qPCR, and xenograft and syngeneic tumor models.Results
CRAT was prioritized through cross-platform convergence of the CRISPR screen with transcriptomic and proteomic signatures of radioresistant cells, and post-treatment tumors with poorer pathological regression showed higher CRAT and nuclear p65 immunohistochemical scores. CRAT manipulation had limited, model-dependent effects on basal proliferation but more pronounced effects after irradiation, where CRAT loss reduced clonogenic survival and was associated with increased oxidative stress and persistent DNA damage. Stable-isotope tracing showed that irradiation increased acetate-to-acetylcarnitine flux and expanded the free coenzyme A pool in control cells, whereas CRAT loss disrupted this acetyl-group buffering. Mechanistically, CRAT catalytic activity helped maintain irradiation-induced p65 Lys310 acetylation, H3K27ac enrichment at NF-κB-responsive loci, and NF-κB-associated transcriptional output through a p300/CBP-sensitive acetylation axis. p65-K310Q rescue and RELA depletion supported p65 acetylation and RELA-dependent transcription as downstream contributors to, rather than sole mediators of, CRAT-dependent radioprotection. In syngeneic MC38 tumors, Crat deletion enhanced the response to fractionated radiotherapy.Conclusions
These findings support CRAT-dependent acetyl-group metabolism as a contributor to an NF-κB-associated radioprotective program and nominate this metabolic dependency as a candidate vulnerability for radiosensitization in colorectal cancer.
Related
- Association of CDKN2A overexpression with poor prognosis, radioresistance, and immunosuppression in colorectal cancer
- High-Glucose Environment Promotes Radioresistance in Colorectal Cancer via SERPINE1-Enhanced DNA Repair and Anti-Apoptosis.
- LncRNA HITT stabilizes SIRT6 to restrain H3/H4 acetylation and suppress colorectal cancer growth
- FABP4 and L-acetylcarnitine as candidate biomarkers for small airway dysfunction in children with obese type 2 asthma: a pilot cross-sectional multi-omics study.
- Chronic Microcystin-LR Exposure Induces Colorectal Inflammation Associated with Macrophage Infiltration and HIF-1α-Related Glycolytic Reprogramming
BibTeX
@article{liu2026cratmediated,
title = {{CRAT-mediated acetylcarnitine shuttling sustains p65 acetylation and NF-κB-associated radioresistance in colorectal cancer.}},
author = {Yixuan Liu and Yu Xiao and Yiran Chen and Chaoxiong Huang and Feifei Lin and Qingyang Zhuang and Hui Li and Peicheng Lin and Lirui Tang and Jinluan Li},
journal = {Molecular cancer},
year = {2026},
month = jul,
doi = {10.1186/s12943-026-02753-z},
url = {https://europepmc.org/article/MED/42958367},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - CRAT-mediated acetylcarnitine shuttling sustains p65 acetylation and NF-κB-associated radioresistance in colorectal cancer.
AU - Yixuan Liu
AU - Yu Xiao
AU - Yiran Chen
AU - Chaoxiong Huang
AU - Feifei Lin
AU - Qingyang Zhuang
AU - Hui Li
AU - Peicheng Lin
AU - Lirui Tang
AU - Jinluan Li
PY - 2026
DA - 2026/07/01
JO - Molecular cancer
DO - 10.1186/s12943-026-02753-z
UR - https://europepmc.org/article/MED/42958367
AB - Background Neoadjuvant chemoradiotherapy is a standard treatment for locally advanced rectal cancer, yet acquired resistance limits durable tumor control. Whether stress-adaptive acetyl-group metabolism contributes to this resistance remains unclear.Methods We performed a genome-wide CRISPR-Cas9 loss-of-function screen under fractionated irradiation and integrated the results with transcriptomic and proteomic profiling of radioresistant colorectal cancer models established by stepwise irradiation. CRAT function was interrogated using genetic perturbation, catalytic-dead reconstitution, acetylation-mimetic p65 rescue, RELA depletion, stable-isotope tracing, free coenzyme A quantification, NF-κB reporter assays, chromatin immunoprecipitation-qPCR, and xenograft and syngeneic tumor models.Results CRAT was prioritized through cross-platform convergence of the CRISPR screen with transcriptomic and proteomic signatures of radioresistant cells, and post-treatment tumors with poorer pathological regression showed higher CRAT and nuclear p65 immunohistochemical scores. CRAT manipulation had limited, model-dependent effects on basal proliferation but more pronounced effects after irradiation, where CRAT loss reduced clonogenic survival and was associated with increased oxidative stress and persistent DNA damage. Stable-isotope tracing showed that irradiation increased acetate-to-acetylcarnitine flux and expanded the free coenzyme A pool in control cells, whereas CRAT loss disrupted this acetyl-group buffering. Mechanistically, CRAT catalytic activity helped maintain irradiation-induced p65 Lys310 acetylation, H3K27ac enrichment at NF-κB-responsive loci, and NF-κB-associated transcriptional output through a p300/CBP-sensitive acetylation axis. p65-K310Q rescue and RELA depletion supported p65 acetylation and RELA-dependent transcription as downstream contributors to, rather than sole mediators of, CRAT-dependent radioprotection. In syngeneic MC38 tumors, Crat deletion enhanced the response to fractionated radiotherapy.Conclusions These findings support CRAT-dependent acetyl-group metabolism as a contributor to an NF-κB-associated radioprotective program and nominate this metabolic dependency as a candidate vulnerability for radiosensitization in colorectal cancer.
SN - 1476-4598
ER -