DEGs with a FDR ≤ 0.05.

Leishmania spp. are intracellular parasites that cause leishmaniasis, a devastating disease with no effective treatment. These parasites are heme auxotrophs and must scavenge this essential cofactor from the host. Transcriptomic analysis of Leishmania major promastigotes cultured in the presence or absence of heme revealed numerous differentially expressed genes. Among those of unknown function, LHR2 (Leishmania Heme Response-2) was the most upregulated gene in response to heme limitation. LHR2 encodes a mitochondrial hemoprotein that likely protects this organelle from elevated levels of reactive oxygen species. It is essential during the promastigote stage, and loss of a single LHR2 allele severely compromises intracellular replication and prevents the development of cutaneous leishmaniasis in mice. This essential function depends on LHR2’s ability to bind heme. Complementation studies in Saccharomyces cerevisiae revealed that LHR2 is an analogue of the yeast Dap1p, although it binds heme in a distinct manner. Importantly, LHR2 displays key structural differences from the most closely related human proteins. These findings highlight LHR2 as a critical factor in parasite survival and pathogenesis, and suggest it as a promising new target for antileishmanial drug development.