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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

HADHA K406 Lactylation Regulates Metabolic Reprogramming and Suppresses Immune Responses in Gastric Cancer.

  • Maoxiao Feng1
  • Qinlian Jiao1
  • Jiankang Zhu2
  • Yidan Ren1
  • Xiaoyu Teng3
  • Xin Su4
  • Zigan Li4
  • Yuxuan Cai1
  • Xiaoyan Liu1
  • Yunshan Wang1
  • Guangyong Zhang2
4 affiliations
  1. 1Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  2. 2Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
  3. 3Department of Clinical Laboratory, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
  4. 4Department of Clinical Laboratory, Cheeloo College of Medicine, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
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Abstract

Gastric cancer (GC) represents a substantial global health challenge and is among the most prevalent and deadly malignancies worldwide. Emerging evidence suggests that protein lactylation plays a pivotal role in the progression of various cancers. However, the specific levels and regulatory mechanisms of protein lactylation in GC remain poorly understood. In this study, we detected elevated pan-lactylation modification levels in GC tissues. Notably, lactylation at the K406 site of hydroxyacyl-CoA dehydrogenase (HADHA) was significantly upregulated in GC tissues. This site-specific lactylation modification enhanced GC progression. Disrupting lactylation at the HADHA K406 site markedly reduced its enzymatic activity, thereby mitigating GC progression by impairing fatty acid β-oxidation and glycolysis. Furthermore, inhibiting HADHA K406 lactylation (HADHA K406la) suppressed the HMG-CoA reductase (HMGCR)-mediated cholesterol synthesis pathway, which, in turn, improved the immunosuppressive tumor microenvironment in GC. Finally, combining an HMGCR inhibitor with a lactate dehydrogenase A (LDHA) inhibitor effectively enhanced the immune response against GC and inhibited tumor progression. In conclusion, this study demonstrated that HADHA K406la regulates GC progression through its impact on metabolic pathways, suggesting its potential as a therapeutic target for GC treatment.

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Cite

BibTeXRIS
BibTeX
@article{feng2026hadha,
  title = {{HADHA K406 Lactylation Regulates Metabolic Reprogramming and Suppresses Immune Responses in Gastric Cancer.}},
  author = {Maoxiao Feng and Qinlian Jiao and Jiankang Zhu and Yidan Ren and Xiaoyu Teng and Xin Su and Zigan Li and Yuxuan Cai and Xiaoyan Liu and Yunshan Wang and Guangyong Zhang},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78291},
  url = {https://europepmc.org/article/MED/42958722},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - HADHA K406 Lactylation Regulates Metabolic Reprogramming and Suppresses Immune Responses in Gastric Cancer.
AU  - Maoxiao Feng
AU  - Qinlian Jiao
AU  - Jiankang Zhu
AU  - Yidan Ren
AU  - Xiaoyu Teng
AU  - Xin Su
AU  - Zigan Li
AU  - Yuxuan Cai
AU  - Xiaoyan Liu
AU  - Yunshan Wang
AU  - Guangyong Zhang
PY  - 2026
DA  - 2026/10/29
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78291
UR  - https://europepmc.org/article/MED/42958722
AB  - Gastric cancer (GC) represents a substantial global health challenge and is among the most prevalent and deadly malignancies worldwide. Emerging evidence suggests that protein lactylation plays a pivotal role in the progression of various cancers. However, the specific levels and regulatory mechanisms of protein lactylation in GC remain poorly understood. In this study, we detected elevated pan-lactylation modification levels in GC tissues. Notably, lactylation at the K406 site of hydroxyacyl-CoA dehydrogenase (HADHA) was significantly upregulated in GC tissues. This site-specific lactylation modification enhanced GC progression. Disrupting lactylation at the HADHA K406 site markedly reduced its enzymatic activity, thereby mitigating GC progression by impairing fatty acid β-oxidation and glycolysis. Furthermore, inhibiting HADHA K406 lactylation (HADHA K406la) suppressed the HMG-CoA reductase (HMGCR)-mediated cholesterol synthesis pathway, which, in turn, improved the immunosuppressive tumor microenvironment in GC. Finally, combining an HMGCR inhibitor with a lactate dehydrogenase A (LDHA) inhibitor effectively enhanced the immune response against GC and inhibited tumor progression. In conclusion, this study demonstrated that HADHA K406la regulates GC progression through its impact on metabolic pathways, suggesting its potential as a therapeutic target for GC treatment.
SN  - 2198-3844
ER  -