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

The review consolidates functional evidence for 15 MAPK homologues in pathogenic Leishmania, connecting them to parasite differentiation, intracellular survival, stress tolerance, motility, virulence and drug response. Rather than treating the MAPK repertoire as a uniform kinase family, it assesses evidence member by member. Review synthesis based on existing literature; no new experimental data are reported.

The authors explicitly distinguish mechanistically established, experimentally validated targets from computationally proposed candidates. It offers readers a tiered judgement of evidence maturity for MAPK targets instead of a flat catalogue. Based on critical assessment of the degree of validation in existing studies.

Structural peculiarities, regulatory architecture and substrate recognition are proposed as potential opportunities for parasite-selective kinase inhibition, while functional redundancy, incomplete kinase-substrate networks, stage-specific signalling and conservation of host MAPK pathways remain substantial obstacles. It presents both the feasibility and the real resistance to selective inhibition rather than one-sided optimism. Synthesis and inference from structural biology and signalling pathway studies.

The review evaluates small-molecule and natural-product inhibitors, drug repurposing and structure-guided approaches, and incorporates contributions from molecular dynamics, AlphaFold-based structural modelling, artificial intelligence and nanotechnology; evidence supporting MAPK10 as a vaccine-associated antigen further broadens the translational relevance of this signalling system. It brings a vaccine direction beyond chemotherapy into the same translational view of this signalling system. Review-level synthesis of existing inhibitor studies and antigen evidence.

This is a review intended for researchers and drug-discovery practitioners seeking an overview of the Leishmania MAPK signalling network and its translational prospects; its conclusions rest on existing literature evidence and are meant to guide subsequent mechanistic studies and target prioritization.

Readers should still watch: the strength of functional evidence varies considerably across MAPK members, kinase-substrate networks remain incomplete, and the impact of stage-specific signalling and host pathway conservation on selectivity needs further study; moreover, this reading is at summary scope without figures or full reference details, so specific experimental conditions and data strength should be verified against the original.