Molecular mechanisms involved in Plasmodium gametocytogenesis

Malaria, a disease caused by protozoa of the genus <i>Plasmodium</i>, remains a major challenge for global public health. The persistence of disease transmission to the mosquito vector depends on the differentiation of asexual blood-stage parasites into gametocytes, a process known as gametocytogenesis. Interrupting this stage of the parasite's life cycle represents a critical strategy for malaria control and eventual eradication. This review aims to consolidate recent advances in the understanding of the complex molecular mechanisms regulating gametocytogenesis in <i>Plasmodium</i>, with a particular focus on <i>P. falciparum</i>. Sexual differentiation is modulated by various factors, including environmental stressors such as the depletion of lysophosphatidylcholine (LysoPC), and is orchestrated through a sophisticated regulatory network. At the transcriptional level, the AP2-G transcription factor functions as a master switch, whose expression is tightly regulated by epigenetic mechanisms, including histone H3K9 trimethylation (H3K9me3) as well as the activity of both heterochromatin protein 1 (HP1) and gametocyte development protein 1 (GDV1). Following commitment, post-transcriptional regulation plays a critical role in further differentiation, including transcript stabilization by RNA-binding proteins such as PfPuf1 and PfPuf2, along with epitranscriptomic modifications such as mRNA methylation (m⁵C and m⁶A), which modulate gene expression. A comprehensive understanding of these interconnected regulatory pathways is essential for the identification of novel therapeutic targets and the development of effective transmission-blocking vaccines.