Metabolic pathway exposes Achilles’ heel in chemotherapy resistance

Researchers from The Wistar Institute and Temple University have identified a previously unknown metabolic mechanism that enables ovarian cancer cells to repair DNA damage and survive chemotherapy - and a potential way to block this process.

Many ovarian tumours resist platinum-based chemotherapy by rapidly repairing DNA damage that would normally be lethal to cancer cells. These DNA repair–proficient cancers are associated with poor prognosis and early recurrence.

Now, scientists have uncovered a surprising driver of this resistance: a metabolite called alpha-ketoglutarate (αKG), which accumulates in these tumours and rewires cellular metabolism in unexpected ways.

Published in Nature, the study [1] shows that αKG activates an enzyme called TMLHE, triggering the production of carnitine. This in turn drives a previously unrecognised metabolic pathway that alters histone acetylation, loosens chromatin structure, and allows DNA repair machinery to access and fix damaged genetic material more efficiently.

When this pathway is blocked - either by inhibiting TMLHE or disrupting carnitine synthesis - cancer cells lose their ability to efficiently repair DNA and become significantly more sensitive to chemotherapy.

The researchers also tested mildronate, a clinically used inhibitor of carnitine synthesis. In mouse models of ovarian cancer, the combination of mildronate and cisplatin significantly reduced tumour burden, while either treatment alone had little effect.

“Everyone in the field would have told us to look at the demethylases. That’s what the literature pointed to. Finding TMLHE was the moment I thought, ‘Okay, this is going to be something bigger than what we expected,’” said Katherine Aird, senior author of the study at The Wistar Institute.

“What we found is that αKG is controlling acetylation through a completely separate route, and that pathway turns out to be essential for DNA repair,” said co-senior author Professor Nathaniel Snyder of Temple University. “It’s a new layer of biology that had not been described before.”

Beyond ovarian cancer, the findings suggest broader implications for cancer biology and ageing, as αKG is known to decline with age and plays a key role in cellular regulation and stem cell function.

The team also identified potential clinical markers of this pathway, showing that high TMLHE expression correlates with poorer progression-free survival, while elevated acetylcarnitine levels in blood samples may help identify patients more likely to resist standard chemotherapy.

By linking metabolism directly to chromatin accessibility and DNA repair, the study opens a new therapeutic angle - targeting cancer metabolism not only to starve tumours, but to disable their ability to repair themselves.

More information online

αKG-mediated carnitine synthesis drives DNA repair via histone acetylation, published in Nature, 2026. Online publication