The MAPK signalling landscape of Leishmania: structural diversity, biological functions and therapeutic potential.

Abstract

The remarkable adaptability of Leishmania throughout its complex life cycle depends on signalling networks that integrate environmental stress, developmental cues, and host-derived signals. Among these, mitogen-activated protein kinases (MAPKs) have emerged as important regulatory nodes, yet their contribution to parasite biology and their value as potential therapeutic targets remain incompletely resolved. This review examines the expanding landscape of Leishmania MAPKs, encompassing 15 homologues across pathogenic species, and synthesizes evidence linking individual kinases to parasite differentiation, intracellular survival, stress tolerance, motility, virulence, and drug response. Rather than treating the MAPK repertoire as a uniform kinase family, we critically assess the extent to which individual members have been experimentally validated and distinguish mechanistically established targets from computationally proposed candidates. Structural peculiarities, regulatory architecture, and substrate recognition offer potential opportunities for parasite-selective kinase inhibition; however, functional redundancy, incomplete kinase-substrate networks, stage-specific signalling, and conservation of MAPK pathways in the host remain substantial obstacles. We further evaluate small-molecule and natural-product inhibitors, drug-repurposing strategies, and structure-guided approaches, while considering emerging contributions from molecular dynamics, AlphaFold-based structural modelling, artificial intelligence, and nanotechnology to drug discovery. Beyond chemotherapy, evidence supporting MAPK10 as a vaccine-associated antigen broadens the translational relevance of this signalling system. Thus, the current findings position Leishmania MAPKs as a multifaceted interface between parasite signalling, adaptation, and therapeutic vulnerability. In this context, future studies should define the signalling dependencies that distinguish essential MAPKs from functionally redundant or context-dependent kinases, thereby facilitating the translation of current mechanistic insights into selective and clinically actionable therapies for leishmaniasis.