| Rank |
Pathway / Target Axis |
Direction |
Primary Effect |
Notes / Cancer Relevance |
Ref |
| 1 |
One-carbon metabolism (methionine cycle → folate cycle coupling) |
↓ one-carbon flux (Met/SAM-linked metabolites) |
Core metabolic constraint |
Nature study shows dietary MR produces controlled, reproducible changes to one-carbon metabolism that alter cancer outcomes |
(ref) |
| 2 |
Nucleotide biosynthesis (purines/thymidylate via one-carbon units) |
↓ nucleotide synthesis capacity |
DNA/RNA synthesis limitation |
Same MR Nature paper links MR-driven one-carbon changes to pathways needed for proliferation and therapy response |
(ref) |
| 3 |
Therapy sensitivity (chemo / targeted one-carbon therapy synergy) |
↑ sensitivity / ↑ efficacy |
Therapeutic potentiation |
Dietary MR influences outcomes and can enhance responses to standard therapies through one-carbon metabolic rewiring |
(ref) |
| 4 |
mTORC1 nutrient sensing (Met/SAM → SAMTOR mechanism) |
↓ mTORC1 signaling when Met/SAM low |
Reduced anabolic growth signaling |
Mechanistic review: SAMTOR senses SAM (derived from methionine) and, when SAM is low, inhibits mTORC1 signaling |
(ref) |
| 5 |
Integrated Stress Response (ISR; ATF4 induction under MR) |
↑ ISR / ↑ ATF4 |
Amino-acid stress adaptation |
MR activates ISR in TNBC cells (eIF2α phosphorylation; ATF4 and targets up), demonstrating stress signaling engagement under methionine restriction |
(ref) |
| 6 |
Glutathione (GSH) / ferroptosis coupling (CHAC1 axis) |
↑ CHAC1 / ↓ GSH / ↑ ferroptosis (context-dependent) |
Redox vulnerability |
Intermittent dietary methionine deprivation augments tumoral ferroptosis; paper links effect to CHAC1 upregulation (CHAC1 promotes GSH degradation) |
(ref) |
| 7 |
Epigenetic methylation capacity (SAM-dependent methylation) |
↓ methylation potential (via ↓ SAM availability) |
Altered gene regulation |
Review focused on dietary methionine and cancer: MR impacts SAM-dependent methylation processes central to biosynthesis/regulation in tumors |
(ref) |
| 8 |
Systemic growth signaling (IGF-1) |
↓ IGF-1 |
Lower systemic pro-growth cue |
Intermittent MR reduces circulating IGF-1 (healthspan paper, but the endocrine direction is explicit and relevant to tumor growth biology) |
(ref) |
| 9 |
Radiation sensitization (clinical feasibility context) |
↑ RT sensitivity (preclinical); feasible in humans |
Translational evidence |
Phase I pilot: MR diet given concurrently with radiation—supports feasibility/safety; paper states preclinical evidence of MRD sensitizing cancer to RT |
(ref) |
| 10 |
In vivo tumor growth |
↓ tumor growth / ↓ progression (model-dependent) |
Demonstrated anti-tumor effect |
Nature MR paper demonstrates MR can influence tumor outcomes in mouse cancer models |
(ref) |