AniView Support Malaria Research: β-hydroxybutyrate inhibits Plasmodium falciparum development and confers protection against malaria in mice

New progress has been made in ketone body–mediated malaria prevention and treatment.

Professor Qijun Chen’s research team from Shenyang Agricultural University published their findings in “Nature Metabolism” (IF = 20.8, CAS Q1 Top journal).

This study provides new insights into the antimalarial effects of β-hydroxybutyrate (βOHB), demonstrating that ketogenic diets and βOHB supplementation can inhibit malaria parasite development and provide protection against malaria infection, offering a new metabolic therapeutic strategy for malaria prevention and treatment.

Malaria, a life-threatening infectious disease caused by Plasmodium parasites, has long posed a threat to human health in tropical and subtropical regions. Currently, resistance of Plasmodium falciparum to artemisinin-based drugs continues to spread, creating an urgent need to develop entirely new prevention and control strategies. Previous studies have demonstrated that host environmental factors, such as dietary restriction, glycolysis inhibition, and high-fat diets, can affect parasite development by regulating the nutrient-sensing mechanisms of Plasmodium. However, the effects of host metabolic variations, particularly ketone body metabolism, on the infectivity of blood-stage malaria parasites have not yet been clearly established.

Ketone body metabolism is a key energy supply pathway in mammals under conditions of glucose deprivation, such as fasting and prolonged exercise. It primarily produces three small molecules: β-hydroxybutyrate (βOHB), acetoacetate (AcAc), and acetone. Among these, βOHB is the most abundant and functionally central ketone body. It not only serves as an energy source but also regulates gene expression by inhibiting histone deacetylases (HDACs), participating in metabolic regulation and protection against oxidative stress. In Plasmodium falciparum, HDACs are key proteins involved in regulating genes associated with parasite development. Their inhibitors have been demonstrated to eliminate malaria parasites both in vitro and in animal models, suggesting that elevated concentrations of βOHB may exert antimalarial effects by interfering with the biological regulatory mechanisms of Plasmodium.

The findings of this study demonstrate that a ketogenic diet (KD) can significantly increase βOHB concentrations in the blood of mice and provide complete protection against Plasmodium berghei infection. Exogenous βOHB supplementation can also significantly prolong the survival of infected mice and suppress parasitemia. More importantly, βOHB can also inhibit the proliferation of human Plasmodium falciparum in vitro in a dose-dependent manner, with a half-maximal inhibitory concentration (IC50) of 7.3 mM, without inducing hemolysis. Mechanistically, βOHB inhibits malaria parasite development through two complementary pathways. At the metabolic level, it significantly reduces nicotinamide adenine dinucleotide (NAD) levels in red blood cells infected with both P. berghei and P. falciparum (iRBCs), disrupting the energy supply of the parasite's glycolysis–gluconeogenesis pathway and oxidative phosphorylation pathway. Supplementation with NAD can completely reverse the inhibitory effect of βOHB on parasite proliferation. At the gene expression level, βOHB downregulates the expression of genes associated with red blood cell invasion by malaria parasites, including merozoite surface proteins (MSPs), apical membrane antigen 1 (AMA1), and rhoptry proteins (ROPs); genes associated with parasite development, such as APiAP2 transcription factors and calcium-dependent protein kinase 6 (CDPK6); and virulence-related genes. Meanwhile, it also suppresses pathways associated with ribosome biogenesis and DNA replication, resulting in the developmental arrest of P. falciparum at the early trophozoite stage and a reduction in merozoite production. Taken together, these findings demonstrate that a ketogenic diet exerts antimalarial effects by increasing βOHB levels, and that βOHB is also effective against human P. falciparum. This study provides a new perspective on malaria prevention and control through a "metabolic therapy" approach and offers an entirely new direction for the prevention and treatment of artemisinin-resistant malaria.

Experiments using Aniview

In this study, the authors used the AniView Multimode In Vivo Imaging System from Guangzhou Biolight Biotechnology Co., Ltd. to image mice infected with P. berghei ANKA-luc and evaluate parasite accumulation in mice fed a ketogenic diet (KD) or a regular diet (RD). The results showed that the bioluminescence signals from parasites in the KD group, representing the extent of parasite accumulation, were significantly lower than those in the RD group. Statistical analysis further confirmed a significant difference between the two groups. These findings visually demonstrate that a ketogenic diet can effectively inhibit the proliferation and accumulation of P. berghei in mice.

DOI: 10.1038/s42255-025-01302-0