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

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.