Lactate-Driven Protein Lactylation Regulates Virulence in Plasmodium falciparum

Lactic acidosis, driven by hyperlactatemia, is a hallmark of severe Plasmodium falciparum malaria, yet its impact on parasitic life cycle and gene expression remains unclear. In mammalian cells, lactate influences transcription through histone lactylation, a novel post-translational modification. In this study, we demonstrate that P. falciparum undergoes lactate-derived lysine lactylation on nuclear proteins, including histones, histone variants, and AP2 transcription factors, with lactylation levels dynamically varying in response to physiological lactate ranges. Through CUT&RUN profiling, we show that elevated lactate enhances chromatin occupancy of lactylated proteins at promoters of genes involved in virulence and cytoadherence. Correspondingly, transcriptomic analyses demonstrated a suppression of these genes in response to elevated lactate, a pattern also evident in clinical isolates from severe malaria patients. Functionally, we demonstrate that high lactate reduces the binding ability of infected erythrocytes to CD36 receptor. Together, our findings reveal protein lactylation as a metabolite-responsive epigenetic mechanism in P. falciparum, linking host metabolic state to transcriptional reprogramming with direct implications for parasite virulence and disease pathogenesis. This study provides genome-wide profiling of lactylation in Plasmodium falciparum 3D7 parasites across ring, trophozoite, and schizont stages supplemented with either 0.5 mM or 8 mM exogenous sodium l-lactate using the Cleavage Under Targets and Release Using Nuclease (CUT&RUN) technique. Parasites were treated for 12 hours and then harvested at ring stage (12-16 hpi), trophozoite stage (28-32hpi) and schizont (40-44 hpi). Both panKla antibody and a site-specific H4K12la antibody were employed, alongside H3K4me3 and H4K12ac as positive controls and IgG as a negative control. These data offer insights into lactylation-mediated epigenetic regulation in malaria parasites and represent the first lactylation CUT&RUN dataset in P. falciparum.