2. Academic Validation
  3. UBE2C-PI3K/AKT-mediated upregulation of MTHFD2 promotes tumor progression in hepatocellular carcinoma

UBE2C-PI3K/AKT-mediated upregulation of MTHFD2 promotes tumor progression in hepatocellular carcinoma

  • Int Immunopharmacol. 2026 Feb 1:170:116081. doi: 10.1016/j.intimp.2025.116081.
Yingying Tong 1,  Qian Liu 2,  Zezhou Zhao 2,  Kangjie Wang 2,  Jing Wang 2,  Baojuan Han 2,  Ke Zhu 2,  Lijun Yang 2,  Chan Zhang 2,  Dong Guo 3,  Dong Yan 2,  Xin Liu 4
Affiliations

Affiliations

  • 1 Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China. Electronic address: [email protected].
  • 2 Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China.
  • 3 Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China.
  • 4 Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China. Electronic address: [email protected].
PMID: 41456492 DOI: 10.1016/j.intimp.2025.116081
Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive liver malignancy with poor prognosis and limited therapeutic options. Methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2), a mitochondrial enzyme involved in one‑carbon metabolism, is frequently upregulated in cancers; however, its role and regulatory mechanisms in HCC remain poorly defined. In this study, we show that MTHFD2 is significantly overexpressed in HCC and correlated with increased tumor cell proliferation and poor prognosis. MTHFD2 knockdown significantly impaired HCC cell proliferation, invasion, and metastasis, while enhancing CD8+ T cell-mediated cytotoxic responses. Mechanistically, UBE2C facilitated PTEN ubiquitination and subsequent degradation, leading to activation of the PI3K/Akt/mTOR signaling cascade and upregulation of MTHFD2 transcription mediated by transcription factor ATF4. MTHFD2 maintained redox homeostasis and upregulated PD-L1 expression, thereby driving tumor development. Inhibition of the UBE2C-MTHFD2 axis suppressed HCC development in vivo models. Furthermore, expression levels of UBE2C and MTHFD2 are positively correlated and independently associated with poor prognosis in HCC patients. Collectively, these findings establish UBE2C as a key upstream regulator of MTHFD2 and highlight MTHFD2 as a promising therapeutic target for HCC.

Keywords

Hepatocellular carcinoma; MTHFD2; PTEN; Tumor progression; UBE2C; Ubiquitination.

Figures
Products