MTHFD2 (Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2)

The immunolabeling method produced consistent results for this group of enzymes, which might lead to successful application in predicting tumor prognosis. Other NADPH-related enzymes, such as glutamate dehydrogenase (GDH), aldehyde dehydrogenase 1 (ALDH1), and dihydrofolate reductase (DHFR), deserve more extensive investigation to elucidate their potential as cancer biomarkers via IHC.

Mitochondrial dysfunction mediated by MTHFD2 in macrophages plays a key role in GBM progression and immune heterogeneity. MTHFD2 represents a potential diagnostic biomarker and therapeutic target for modulating GBM immune infiltration.

Pathway analyses highlighted membrane-proximal processes (external plasma membrane and IgG binding) and a 16p11.2 signal. This integrative analysis identified CCR2-ARTN as a mechanistically supported immune-inflammation axis contributing to AML risk, offering a potential therapeutic target and warrants direct validation in primary CD62L + myeloid DCs.

Hypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation of MTHFD2 and SHMT2, linking hypoxia, redox signaling, and one-carbon metabolism. These findings suggest a potential therapeutic axis that could be exploited for TNBC treatment.

Mechanistically, MTHFD2 promotes cSCC progression by sustaining glycolytic metabolism and redox homeostasis, while also exerting a non-metabolic function through interaction with fatty acid synthase (FASN) to activate the PI3K-AKT signaling pathway. Importantly, pharmacological inhibition of MTHFD2 effectively suppressed cSCC cell proliferation in vitro and tumor growth in vivo, highlighting MTHFD2 as a promising therapeutic target.

In conclusion, we proposed a non-canonical function of MTHFD2, which bound to and stabilized the mRNA of TOP2A. Targeting MTHFD2 triggered excessive mitophagy and cell apoptosis in GBM via destabilizing TOP2A mRNA.

Targeting STAT6 or MTHFD2 suppressed tumor growth in TKIs-resistant patient-derived xenograft models. Collectively, our findings identify the SOX4-STAT6-MTHFD2 axis as a critical driver of HCC progression and therapeutic resistance, offering a promising target for intervention in refractory HCC.

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.

Our findings suggest that SUCD1m, MTHFDm and ORNTArm are important metabolic biomarkers that could serve as predictive indicators for ICI response and, if validated in a larger cohort, may guide the development of targeted therapies to enhance treatment efficacy for gynecologic cancer patients. This study highlights the use of genome-scale metabolic modeling to identify clinically relevant biomarkers and improve therapeutic strategies.

This review provides a retrospective on four decades of advancements on MTHFD2 that have revealed its key roles in the folate pathway, amino acid and redox homeostasis, and the metabolism of cancer and immune cells. We trace the initial biochemical characterization of the enzyme, highlight pivotal discoveries regarding MTHFD2's metabolic and non-canonical roles, and discuss the current state of knowledge and future prospects.

Critically, pharmacological inhibition of MTHFD2 (e.g., DS18561882) blocks FOXO1 degradation, establishing the MTHFD2-FOXO1 axis as a promising therapeutic target for TSCC through its novel metabolic-epigenetic regulatory mechanism. Implications: This study identifies the MTHFD2-FOXO1 axis as a druggable metabolic-epigenetic pathway in TSCC, providing both a prognostic marker and a therapeutic target.

The accurate risk model stratified patients: high-risk correlated with suppressed immunity (p < 2.2e-16), elevated TIDE (p = 5.4e-14), and higher CI.1040 IC50 (cor = 0.63, p < 0.0001)...Risk score, age, race, N/M-stage were independent factors. Seven prognostic genes effectively predicted BRCA prognosis with independent prognostic factors.