Malaria kills around 600,000 people every year, most of them children in Africa. But even when the infection begins to come under control, the danger may not be over. More than 45% of children with severe malaria develop acute kidney injury, a complication that significantly increases the risk of death. Yet the mechanisms responsible for this damage remain poorly understood, and there are currently no specific treatments to prevent it.

A new project – “Exploring ferroptosis protection by bilirubin in malaria-associated acute kidney injury”- led by GIMM Group Leader Miguel Soares, in collaboration with pediatrician Andrea Conroy, from the Ryan White Center for Pediatric Infectious Diseases and Global Health at Indiana University School of Medicine, in the United States, aims to investigate this problem. Funded by the “la Caixa” Foundation, the research will explore whether one of the body’s natural responses to malaria – the production of bilirubin, a yellow pigment – can protect the kidneys and help identify children at risk of developing severe kidney injury at an early stage.

“This funding builds on a line of research we started around 20 years ago, when we discovered that red blood cells destroyed by Plasmodium infection release heme, a highly toxic molecule that contributes to severe malaria,” explains Miguel Soares.

“For 2,500 years, jaundice has been interpreted as a sign that the body is failing. Our work, published in Science and iScience, shows that in malaria the opposite may be true: bilirubin accumulation is not merely a by-product of the disease, but an adaptive response that limits its severity. The body is fighting back. Working with Andrea Conroy, we now have a unique opportunity to investigate whether this mechanism also operates in children with malaria and whether it could one day be harnessed to combat this ancient disease. This project is the bridge between that discovery and the children in Uganda who need it most,” he adds.

Bilirubin is best known as the yellow pigment that accumulates in the blood during jaundice. But for Miguel Soares, it is much more than a sign of disease. His laboratory has previously shown that this molecule can help fight malaria by killing Plasmodium, the parasite responsible for the infection. The new project will explore another potential protective role: could bilirubin also protect the kidneys themselves?

“We want to understand how bilirubin protects the kidney from cell death,” explains Miguel Soares.

In experiments in mice, the researchers observed that when bilirubin production is specifically eliminated in the kidneys, malaria infection leads to acute kidney injury and the animals die. However, when the animals are given a molecule that protects against cell death, they are protected. “Bilirubin is effectively protecting against cell death,” says the researcher.

The team has also compared blood plasma from its experimental models with samples from children with severe malaria and kidney injury, collected through Andrea Conroy’s research program in Uganda. The researchers identified several molecules shared by both groups that could serve as potential biomarkers of kidney injury.

The next step is to determine whether these molecular signatures appear early enough to predict which children will develop severe or persistent kidney damage. To do this, researchers will use advanced lipidomics techniques to analyze thousands of lipid molecules throughout the course of infection and identify patterns that emerge before significant kidney damage occurs. The potential biomarkers will then be assessed using samples from children with severe malaria.

The project will also investigate, at the single-cell level, how bilirubin produced in the kidneys influences interactions between kidney cells and the immune system. By combining genetic approaches with single-cell gene expression analysis, the team hopes to understand the mechanisms through which bilirubin changes the behavior of cells involved in kidney injury.

Ultimately, the goal is to turn this knowledge into a clinically useful tool. Imagine a child who appears to be recovering from malaria: analyzing specific markers could help doctors recognize that the child remains at risk of kidney damage and intervening before the injury becomes irreversible. For a disease that continues to claim hundreds of thousands of lives every year, being able to anticipate kidney injury could make a critical difference. And bilirubin, long regarded primarily as a sign of illness, may prove to be part of the body’s own defense system.