Figure Walkthrough

Figures A & B — Explained

A detailed, annotated walkthrough of the two key panels from Lisci et al. 2026 — showing what happens inside a cell when FBXW7 is working normally (Figure A) versus when it is mutated or lost (Figure B).
Based on information retrieved from PubMed · Lisci M et al. Molecular Cell 2026; 86(5):901–916. DOI: 10.1016/j.molcel.2026.02.002

Figure A FBXW7 Functional — Metabolic Flexibility

Molecular Pathway — Normal State

FBXW7 is active — the gatekeeper is on duty

FBXW7 is a tumor suppressor — think of it as a cleanup crew that tags unwanted proteins for destruction. In this healthy state it's fully functional.

c-MYC gets tagged and destroyed

FBXW7 attaches ubiquitin tags (Ub) to the oncogene c-MYC, marking it for the cell's recycling machinery. c-MYC levels stay low. This matters because c-MYC, when abundant, shuts off the genes the cell needs for metabolic flexibility.

Pyruvate Carboxylase (PC) is freely expressed

With c-MYC held in check, the PC gene promoter in the nucleus stays open. The cell reads the PC gene, produces mRNA, and manufactures the pyruvate carboxylase enzyme.

Biotin activates pyruvate carboxylase

Biotin (Vitamin B7) is a required cofactor for PC — it must be attached to the enzyme for it to work. With PC expressed and biotin present, the enzyme is fully active.

Pyruvate takes the bypass route into the TCA cycle

Active PC converts pyruvate → oxaloacetate (OAA), feeding the TCA cycle directly. This is the glutamine bypass — the cell doesn't need glutamine to run its energy engine.

TCA cycle runs — glutamine is optional

The TCA cycle in the mitochondria is fully fuelled via the pyruvate bypass. Glutamine can still be used, but the cell doesn't depend on it. This is metabolic flexibility.

✅ Outcome — Figure A

The cell can survive and grow with or without glutamine. It is metabolically flexible. This is the normal, healthy state — and the state that FBXW7 actively maintains.

Figure B FBXW7 Mutated or Lost — Glutamine Addiction

Molecular Pathway — Mutant State

FBXW7 is mutated or deleted — the gatekeeper is gone

A mutation in the FBXW7 gene (one of the most common tumor suppressor mutations in human cancer) means the cleanup crew is disabled. It can no longer tag proteins for destruction.

c-MYC accumulates unchecked

Without FBXW7 to degrade it, c-MYC builds up to abnormally high levels. c-MYC is a powerful cancer driver — high c-MYC normally accelerates cell growth, but here it also has a destructive side effect on metabolism.

c-MYC recruits a silencing complex to the PC gene

High c-MYC recruits three proteins — MAX, MNT, and SIN3A — to the PC gene's promoter in the nucleus. Together they act as a lock, physically blocking the gene from being read. This is a key mechanistic discovery of the Lisci paper.

PC gene promoter is silenced — no enzyme produced

The PC gene promoter is switched off. No mRNA is made, no pyruvate carboxylase enzyme is produced. Even if biotin is present, it has nothing to activate — the bypass route is permanently closed.

Pyruvate cannot enter the TCA cycle

Without pyruvate carboxylase, pyruvate cannot be converted to oxaloacetate. The alternative on-ramp to the TCA cycle is gone. Pyruvate piles up with nowhere useful to go.

The cell depends entirely on glutamine to fuel the TCA cycle

Glutamine is now the only route into the TCA cycle. The cell has no backup. It is completely addicted to glutamine — remove it, and the cell dies. This is a metabolic vulnerability that cancer therapies can potentially exploit.

⚠ Outcome — Figure B

The cell is glutamine-addicted. It cannot survive without it. FBXW7-mutant cancers (colorectal, T-cell leukemia, cholangiocarcinoma) are predicted to share this vulnerability — making them potential targets for glutamine-blocking therapies like CB-839/telaglenastat.

Figure A vs Figure B — Side by Side

Component	Figure A — FBXW7 Functional	Figure B — FBXW7 Mutated
FBXW7	✅ Active — degrades c-MYC	❌ Mutated / lost — no function
c-MYC level	Low — continuously degraded	High — accumulates unchecked
MAX·MNT·SIN3A	Not recruited — PC gene open	Recruited to PC promoter — gene locked
PC gene promoter	🟢 Active — mRNA produced	🔴 Silenced — no mRNA
Pyruvate Carboxylase (PC)	Expressed and functional	Not expressed — absent
Biotin	Activates PC → bypass route open	Present but useless — no PC to activate
Pyruvate	Converted to OAA → enters TCA	Blocked — bypass route closed
TCA Cycle fuelling	Pyruvate bypass + glutamine (optional)	Glutamine only — no bypass
Glutamine dependence	Optional — cell can survive without it	⚠ Required — cell dies without it
Overall state	Metabolic flexibility	Glutamine addiction

The Plain English Story

Think of a city with two roads leading to the power station. Road 1 (glutamine) is the main highway. Road 2 (the pyruvate bypass via PC and biotin) is a side road that can handle traffic if the main highway is blocked.

Figure A is a city where both roads are open. FBXW7 is the traffic authority keeping everything running. Even if you close Road 1 (remove glutamine), traffic reroutes down Road 2 and the power station keeps running. The city is resilient.

Figure B is what happens when the traffic authority (FBXW7) is taken out. c-MYC — a rogue developer — moves in and permanently blocks Road 2. Now only Road 1 exists. If Road 1 gets cut off, the city loses power and collapses. The city is fragile — and that fragility is the therapeutic opportunity.

The Lisci paper's key contribution is explaining precisely why Road 2 gets blocked: c-MYC recruits the MAX·MNT·SIN3A complex to physically lock the gate (silence the PC gene promoter). This is the molecular mechanism, discovered for the first time in this 2026 study.

Based on information retrieved from PubMed · DOI: 10.1016/j.molcel.2026.02.002