Researchers discover that bilirubin, usually seen as a “waste” of the organism, protects against malaria by killing the parasites that cause the disease.

It is common for patients with severe malaria to develop jaundice — a condition manifested by the yellowing of the skin and eyes, due to the accumulation of the yellow pigment bilirubin, a substance considered a “waste product” of the organism. Now, in a study published today in the scientific journal Science, the team led by Miguel Soares, principal investigator at GIMM (Gulbenkian Institute for Molecular Medicine), discovered that this accumulation is, in fact, an adaptive response of the body that provides protection against malaria by killing the parasites responsible for the disease. This innovative discovery reveals an unexpected host defense mechanism that can be explored as a therapeutic strategy in future malaria treatments.

The Plasmodium genus parasites, which cause malaria, infect and multiply inside the red blood cells circulating in the blood. In these cells, they feed on hemoglobin — the protein that uses iron, contained within a molecular structure called heme, to transport oxygen. At the end of their expansion cycle, they cause the lysis (rupture) of red blood cells, releasing the remaining hemoglobin that they did not ingest into the bloodstream.

Miguel Soares’ laboratory has demonstrated over the years that when hemoglobin is released into the bloodstream, it releases heme, which is highly toxic to the host and is the cause of the development of severe forms of malaria. To prevent heme accumulation in circulation, the host induces a series of complex biochemical reactions that culminate in the production of bilirubin, a yellow pigment that was thought to be nothing more than a toxic “waste product”.

Conjugation of bilirubin in the liver allows its excretion in the intestine and limits bilirubin accumulation in circulation. When there is bilirubin accumulation in circulation, it is considered to be indicative of liver dysfunction. This association contributed for centuries to the idea that jaundice is nothing more than a pathological (disease-causing) response. However, a growing number of discoveries have been demonstrating that bilirubin has several important biological functions, which led the team to explore this hypothesis in the context of malaria. “To our amazement, we discovered that perhaps the most important function of bilirubin is to protect us against malaria through a mechanism we did not anticipate: it kills the parasite,” explains Miguel Soares, coordinator of the study.

Ana Figueiredo, the first author of the study who is completing her PhD with Miguel Soares at GIMM, initially discovered that asymptomatic malaria presented high levels of bilirubin in plasma. In mice, she observed a similar response, with increased bilirubin levels in response to infection, which conferred protection against the disease. In contrast, mice unable to produce bilirubin died from malaria. However, when bilirubin was administered to them, they became resistant to the disease. These results clearly demonstrate that this molecule plays a central role in protecting against malaria. “Through various complementary experiments, both in vivo and in vitro, we demonstrated that bilirubin blocks the proliferation and virulence (ability to induce disease) of Plasmodium parasites within red blood cells, preventing them from feeding and producing energy, which leads to their death,” explains Ana Figueiredo.

Malaria continues to be a disease with high mortality globally, especially among children under five. In 2023 alone, the World Health Organization estimated around 560,000 malaria deaths worldwide. “Discovering that a molecule produced by the body itself during infection can protect against malaria gives us a new perspective on the body’s defense mechanisms and opens up exciting possibilities for the future. Perhaps one day, this discovery could lead to new therapeutic approaches. I am extremely happy to have contributed to something so important,” shares Ana Figueiredo. “This discovery opens doors to explore to what extent this natural defense strategy of the organism can be used therapeutically, in order to alleviate the enormous impact of malaria on human populations,” concludes Miguel Soares.

Figueiredo A, Rastogi ST, Ramos S, Nogueira F, De Villiers K, Gonçalves de Sousa AG, Votborg-Novél L, von Wedel C, Tober-Lau P, Jentho E, Pagnotta S, Mesquita M, Cardoso S, Bortolussi G, Muro AF, Tranfield EM, Thibaud J, Duarte D, Sousa AL, Pinto SN, Kitoko J, Mombo-Ngoma G, Mischlinger J, Junttila S, Alenquer M, Amorim MJ, Vasavda C, Bosma PJ, Violante S, Drotleff B, Paixão T, Portugal S, Kurth F, Elo LL, Paul BD, Martins R, Soares MP (2025). A metabolite-based resistance mechanism against malaria. Science. DOI: 10.1126/science.adq6741