How Iron Reprograms Fat Cells to Drive Cancer Cachexia

Cachexia, a serious condition marked by profound weight loss, muscle wasting, and fatigue, affects many people with advanced cancer and is a major contributor to cancer-related illness and death. Now, researchers at Columbia University have identified an unexpected molecular pathway in fat cells that helps drive this condition.  

The study, published in Nature Cancer, reveals that iron regulates an enzyme called methionine sulfoxide reductase A (MSRA), which controls how fat cells handle energy,  either storing it away  or shifting  to energy-burning. In laboratory mice with pancreatic cancer, disrupting the MSRA pathway prevented much of the fat and muscle loss that is associated with the disease. The mice also lived longer, even though the tumors themselves didn’t change.  

The project began with an observation in mouse models of pancreatic cancer in the lab. 

“We realized that tumor size alone was actually a poor predictor of when the animals would become critically ill,” says Christine Chio, PhD, assistant professor of genetics and development at Columbia University and senior author of the study. “What was much more striking was that, shortly before they died, they would rapidly lose ten to twenty percent of their body mass. That made us ask what was driving this sudden decline.”  

Chio and her colleagues began examining fat tissue in the mice in detail. Under normal circumstances, white fat, which has pale white or yellow color, stores energy, a biological back-system designed to supply fuel when food is scarce. Brown fat does the opposite job, burning calories to produce heat, a response that can occur in mammals exposed to long periods of cold.   

In the mouse models , the researchers noticed that white fat was undergoing “browning”, shifting to an energy-burning program even in the absence of cold. At the same time, they saw that iron accumulated within the fat tissue.  

“That immediately caught our attention because iron is closely linked to thermogenic metabolism,” says Chio. “We began to wonder whether changes in iron metabolism might be helping reprogram these fat cells.”  

Using biochemical and chemical-proteomic approaches, the researchers uncovered changes in an amino acid called methionine, which is found in many proteins. They found that the methionine was undergoing a process called oxidation that can act like molecular switches, altering how proteins function.  

“You can think about protein oxidation a little like rusting,” says Chio. “But in cells, these oxidative marks can be precisely placed and removed, and that can change the activity of the protein.”  

At the center of the oxidation pathway was MSRA, an enzyme that works to remove oxidative marks from methionine molecules. The researchers found higher than normal levels of MSRA in the fat of mice with pancreatic cancer. They also found that MRSA’s activity can be controlled by iron. The result is a molecular circuit connecting iron levels, MSRA, protein oxidation, and the loss of energy stores during cancer.

They traced the pathway one step further, finding that MSRA controls the oxidation state of key methionine molecules in cell signaling protein called protein kinase A, or PKA. In fat cells, PKA drives the browning process from energy storage to energy use. When those methionines in PKA are oxidized, the browning is turned off. When MSRA stripped away the oxidative marks, PKA was able to turn on the browning program, pushing white fat cells toward an energy-burning state.  

The result is a molecular circuit connecting iron levels, MSRA, protein oxidation, and the loss of energy stores during cancer.  

To test whether the pathway actually contributes to cachexia, the researchers genetically engineered their mice with pancreatic cancer to lack MSRA in fat tissue. These animals showed substantially less browning, retained more fat and muscle mass, and survived longer than mice with normal MSRA—even though the tumors grew to similar sizes in both.  

That result changed how Chio thought about the relationship between the tumor and the rest of the body.  

“As a cancer biologist, I had always tended to think of survival primarily as a consequence of how large or aggressive the tumor was,” she says. “But here, we could improve survival without changing tumor burden. What changed was the animals’ body composition and their ability to withstand the disease.”  

The findings have opened several new directions for the laboratory. One major question is how a tumor in the pancreas triggers this metabolic program in distant fat tissue.  

“The tumor and the adipose tissue are physically separated, so we want to understand how that signal travels through the body,” says Chio. “Circulating factors are one possibility, but neural communication is another. We are now investigating both.”  

The work also raises the possibility of treating cancer in a fundamentally different way: not only by attacking the tumor, but by protecting the rest of the body from the consequences of the disease, like cachexia.  

The researchers are now exploring strategies to interfere with the MSRA pathway using small molecules and peptides, as well as testing whether preserving body composition can improve how patients respond to therapies that directly target pancreatic tumors.  

“We are not suggesting that treating cachexia replaces treating the cancer,” Chio says. “The idea is that the two may need to be treated together. If we can preserve fat and muscle while also targeting the tumor, we may be able to help patients tolerate treatment better and potentially keep those treatments effective for longer."