2-methylbutanal remodels arachidonic acid metabolism and antitumor immunity through ENO1 in colorectal cancer
- 1Endoscopy Center, Zhongshan Hospital Fudan University, Shanghai, China
- 2Health Management Center, Zhongshan Hospital, Fudan University, Shanghai, China
- 3Endoscopy Center, Zhongshan Hospital Xuhui Branch, Fudan University, Shanghai, China
Abstract
Background: Active aldehydes are increasingly recognized as bioactive metabolites, but their roles in tumor immune regulation remain poorly defined. In colorectal cancer (CRC), prostaglandin metabolism contributes to immune suppression, whereas its upstream metabolic regulators are incompletely understood. Here, we investigated 2-methylbutanal (2-MBTL), a branched-chain small-molecule aldehyde, in CRC.
Methods: The antitumor and immunoregulatory effects of 2-methylbutanal (2-MBTL) were examined in CRC cell systems and mouse models. Its molecular target and downstream pathway were investigated using target-identification assays, RNA interaction analyses, genetic manipulation, transcriptomic profiling, and PGE2 supplementation.
Results: 2-MBTL suppressed CRC growth at well-tolerated doses, increased tumor immunogenic signals, enhanced intratumoral CD8⁺ T-cell infiltration and effector activity, and reduced suppressive myeloid populations. Its direct antiproliferative effect was limited, whereas its antitumor activity was markedly weakened in immunodeficient mice or after CD8⁺ T-cell depletion. Mechanistically, 2-MBTL bound ENO1 and impaired its association with YAP1 mRNA, reducing YAP1 protein expression without substantially altering ENO1 abundance or glycolysis-associated readouts. This was accompanied by increased HPGD expression and reduced PGE2 levels. ENO1 overexpression attenuated the effects of 2-MBTL, while exogenous PGE2 partially reversed tumor suppression and immune remodeling. In human CRC tissues, ENO1 and HPGD showed opposing associations with CD8⁺ T-cell infiltration and survival. 2-MBTL also enhanced the efficacy of PD-1 blockade.
Conclusions: 2-MBTL promotes CD8⁺ T-cell-dependent antitumor immunity by modulating ENO1-associated post-transcriptional regulation and suppressing YAP1-related PGE2 metabolism.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08762-2.
Related
- Macrophage-specific TRAF6 deletion mitigates DSS-induced colitis and is associated with reduced Enterococcus abundance and altered arachidonic acid metabolism.
- Jiegeng decoction ameliorates COPD-like pulmonary injury in association with changes in PPARγ expression, arachidonic acid metabolism, and gut microbial composition
- Early-life colonization by enterotoxigenic Bacteroides fragilis remodels gut epithelial stem cell states to drive colorectal cancer susceptibility
- A defined microbial community remodels host metabolism and pathogen resistance in Caenorhabditis elegans
- Two Genomes, One Metabolome: Mitonuclear Incompatibility Remodels Developmental Metabolism and Fitness in Drosophila
BibTeX
@article{kam20262methylbutanal,
title = {{2-methylbutanal remodels arachidonic acid metabolism and antitumor immunity through ENO1 in colorectal cancer}},
author = {Sikei Kam and Baohui Song and Zhanghan Chen and Jingyi Liu and Shilun Cai and Bing Li and Mingyan Cai and Zhipeng Qi and Yunshi Zhong},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08762-2},
url = {https://doi.org/10.1186/s12967-026-08762-2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - 2-methylbutanal remodels arachidonic acid metabolism and antitumor immunity through ENO1 in colorectal cancer
AU - Sikei Kam
AU - Baohui Song
AU - Zhanghan Chen
AU - Jingyi Liu
AU - Shilun Cai
AU - Bing Li
AU - Mingyan Cai
AU - Zhipeng Qi
AU - Yunshi Zhong
PY - 2026
DA - 2026/08/11
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08762-2
UR - https://doi.org/10.1186/s12967-026-08762-2
AB - Background: Active aldehydes are increasingly recognized as bioactive metabolites, but their roles in tumor immune regulation remain poorly defined. In colorectal cancer (CRC), prostaglandin metabolism contributes to immune suppression, whereas its upstream metabolic regulators are incompletely understood. Here, we investigated 2-methylbutanal (2-MBTL), a branched-chain small-molecule aldehyde, in CRC. Methods: The antitumor and immunoregulatory effects of 2-methylbutanal (2-MBTL) were examined in CRC cell systems and mouse models. Its molecular target and downstream pathway were investigated using target-identification assays, RNA interaction analyses, genetic manipulation, transcriptomic profiling, and PGE2 supplementation. Results: 2-MBTL suppressed CRC growth at well-tolerated doses, increased tumor immunogenic signals, enhanced intratumoral CD8⁺ T-cell infiltration and effector activity, and reduced suppressive myeloid populations. Its direct antiproliferative effect was limited, whereas its antitumor activity was markedly weakened in immunodeficient mice or after CD8⁺ T-cell depletion. Mechanistically, 2-MBTL bound ENO1 and impaired its association with YAP1 mRNA, reducing YAP1 protein expression without substantially altering ENO1 abundance or glycolysis-associated readouts. This was accompanied by increased HPGD expression and reduced PGE2 levels. ENO1 overexpression attenuated the effects of 2-MBTL, while exogenous PGE2 partially reversed tumor suppression and immune remodeling. In human CRC tissues, ENO1 and HPGD showed opposing associations with CD8⁺ T-cell infiltration and survival. 2-MBTL also enhanced the efficacy of PD-1 blockade. Conclusions: 2-MBTL promotes CD8⁺ T-cell-dependent antitumor immunity by modulating ENO1-associated post-transcriptional regulation and suppressing YAP1-related PGE2 metabolism. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08762-2.
SN - 1479-5876
ER -