Some ketogenic diets found to cause mitochondrial stress and lead to inflammation

New University of Cincinnati Cancer Center research found a ketogenic diet high in long-chain saturated fatty acids can increase inflammation.

Led by Cancer Center Director David Gius, MD, PhD, the study was published Nov. 13  in the journal Science Advances.

What was the research methodology?

A ketogenic diet is high in fat and low in carbohydrates, with the goal of entering ketosis, a metabolic state where the body burns fat and ketones for fuel instead of glucose. While many previous studies have demonstrated anti-inflammatory benefits from a ketogenic diet, other studies have shown increased inflammation and other harmful effects. Gius and colleagues have identified a potential factor contributing to these divergent outcomes.

“We followed the research data while studying a different aspect of ketogenic diets and found something unexpected,” said Gius, who also serves as professor in the Department of Radiation Oncology in UC’s College of Medicine and is a UC Health physician. “Our previous studies have found that all ketogenic diets are not the same, with different fats causing different metabolic changes.”

In this study, Gius and his team administered ketogenic diets comprising different fatty acids to mice animal models and individual fatty acids to tissue culture models.

What were the results?

“We found that long-chain saturated fatty acids seem to favor an inflammatory immune response, whereas unsaturated and medium-chain fatty acids tend to favor anti-inflammatory characteristics.”

The findings demonstrate that the observed increase in inflammation is mediated through mitochondrial stress signaling and activation of immune cells. When these findings are combined with those in the team’s previous publications in Science Advances (2024) and Cell Reports (2025), it suggests that multiple factors may need to be considered to achieve the desired outcome on a ketogenic diet, including dietary sources of fat.

In the context of cancer, Gius said ketogenic diets may alter tumor microenvironments in a way that improves immunotherapy treatment outcomes. A clinical trial is underway at UT Health San Antonio, where Gius began the research, and will open soon at the Cancer Center to learn more.