SHMT2 (Serine Hydroxymethyltransferase 2)

In the HGC27 xenograft model, 15 mg/kg A9 achieved 98.78% tumor growth inhibition (TGI). Collectively, A9 integrates NO-mediated ROS induction and FOCM inhibition, emerging as a promising lead compound for the preclinical development of gastric cancer therapeutics.

SHMT depletion in RasV12DlgRNAi cells causes DNA and chromosome damage and renders these cells sensitive to genotoxic stressors such as X-rays or hydroxyurea...Taken together, our data suggest that a diminished SHMT activity may drive the progression of RasV12DlgRNAi cancers through ROS-induced genome instability. Additionally, our study points to a novel gene-nutrient interaction, SHMT-PLP, that impacts cancer growth with potential therapeutic implications.

Finally, preclinical investigations revealed that some amplification events (CDK4 and SHMT2) decrease susceptibility to drugs that directly target the amplified gene products and increase susceptibility to drugs targeting proteins that function in signaling pathways downstream of these amplified gene products. These combined studies in alveolar rhabdomyosarcoma emphasize the biological and clinical complexities of gene amplification in cancer.

Moreover, the combination of 1G244 and anti-CTLA-4 therapy further enhanced antitumor immunity, highlighting a potential synergistic therapeutic strategy. Collectively, our findings define a novel DPP9-BRISC-SHMT2 regulatory axis in PD-L1 transcriptional control and identify 1G244 as an alternative combinatorial strategy to enhance the efficacy of cancer immunotherapy.

The findings herein demonstrated that mitochondrial uncouplers inhibit MSCP through FTO-dependent m6A demethylation. This work identified mitochondrial uncoupling as a novel and promising therapeutic approach for promoting m6A demethylation and targeting MSCP in metastatic breast cancer.

Finally, molecular docking and dynamics simulations identified piceid as a putative dual inhibitor of G6PD and SHMT2, with favorable binding free energies (-35.53 and -56.49kcal/mol, respectively). Our study establishes a previously unrecognized AAM‑driven subtype, provides a robust prognostic tool, and proposes a first‑in‑class dual‑targeting strategy, highlighting the therapeutic potential of targeting metabolic vulnerabilities in aggressive breast cancer.

Therapeutic strategies targeting metabolic vulnerabilities-including SSP blockade, cholesterol homeostasis disruption, and ferroptosis induction-show synergistic effects with conventional agents like temozolomide. This review highlights the intertwined metabolic circuits in GBM and explores their translational potential as targets for precision therapy.

In functional measurements, HDAC suppression primarily increased excitability, while SIRT suppression decreased excitability, in line with transcriptomic links. Our analysis offers insights about the role of epigenetic modifiers in regulating cardiac electrophysiology and informs the utility of hiPSC-CM as a scalable experimental model for cardiotoxicity testing of HDAC inhibitors.

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.

SHMT2 overexpression counteracted the effects of GEMIN5 knockdown, while GEMIN5 overexpression prominently reversed the regulatory effects of SHMT2 knockdown on β-catenin and GSK3β protein expression. GEMIN5-mediated m7G modification stabilizes high SHMT2 expression, which inhibits CRC cell ferroptosis and activates the Wnt/β-catenin signaling pathway in vitro.

Besides the purine metabolism, we observed that valine, leucine and isoleucine biosynthesis and degradation, TCA cycle, and propanoate metabolism were among the top pathways of DMs. In summary, we highlight the important roles of SHMT2 in HT-1376 cells and identified its downstream molecular targets, which are associated with the development of BLCA and can be used as therapeutic targets of BLCA in future.