2. Academic Validation
  3. NLRP12 decreases TRIM25-mediated HK2 degradation to promote glycolysis and H3K18la in gastric cancer

NLRP12 decreases TRIM25-mediated HK2 degradation to promote glycolysis and H3K18la in gastric cancer

  • Cell Death Dis. 2025 Aug 13;16(1):615. doi: 10.1038/s41419-025-07923-3.
Linsen Zhou # 1,  Zhiqiang Wang # 2 3 4,  Yang Huang # 5,  Xinyi Zhang 1,  Haohai Jiang 1,  Zhiyuan Guo 1,  Guangjun Zhou 6,  Haofeng Liu 7
Affiliations

Affiliations

  • 1 Department of General Surgery, The Yancheng Clinical College of Xuzhou Medical University & The First People's Hospital of Yancheng, Yancheng, China.
  • 2 Department of General Surgery, Tumor Hospital Affiliated to Nantong University & Nantong Tumor Hospital, Nantong, China.
  • 3 Graduate School of Dalian Medical University, Dalian, China.
  • 4 Nanjing Medical University Affiliated Changzhou Second People's Hospital, Changzhou, China.
  • 5 Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University & The First People's Hospital of Yancheng, Yancheng, China.
  • 6 Department of General Surgery, The Yancheng Clinical College of Xuzhou Medical University & The First People's Hospital of Yancheng, Yancheng, China. pwkzgj@163.com.
  • 7 Department of General Surgery, Tumor Hospital Affiliated to Nantong University & Nantong Tumor Hospital, Nantong, China. lhf19870922@163.com.
  • # Contributed equally.
PMID: 40796546 DOI: 10.1038/s41419-025-07923-3
Abstract

Gastric Cancer is the most common primary malignant tumor of the digestive system. Recent studies have shown that targeting tumor cell metabolic reprogramming is a key Cancer treatment strategy. NLR family pyrin domain containing 12 (NLRP12) is related to innate immunity, inflammation and tumorigenesis, but its role in the progression of gastric Cancer remains unclear. The present study revealed that NLRP12 was highly expressed in gastric Cancer tissues and cells, as well as positively correlated with poor patient prognosis and survival. NLRP12 promoted the progression of gastric Cancer mainly by promoting the metabolic reprogramming of gastric Cancer cells, the expression of histone H3 lysine 18 lactylation (H3K18la) and the stabilization of Hexokinase 2 (HK2), a crucial enzyme in glycolysis. In the present study, NLRP12 competes with HK2 for binding to TRIM25, selectively reducing the K63-linked ubiquitination of HK2. Moreover, NLRP12 also exerted a significant cancer-promoting effect in mouse models. In summary, the present study demonstrated that NLRP12 prevents TRIM25 from mediating the K63-linked ubiquitination of HK2, which inhibits HK2 degradation through the autophagosome-lysosome pathway, thereby increasing its protein stability. These changes increase lactic acid production and induce H3K18la, which increases Myc transcription, thereby advancing gastric Cancer progression. These findings reveal a novel cancer-promoting mechanism of NLRP12, potentially leading to the identification of new therapeutic targets for gastric Cancer treatment.

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