Pentalinonsterol alters immune transcriptomic profiles and modulates the Nrf-2 pathway in Leishmania major infected...

Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the genus Leishmania and remains a significant global health burden due to limited therapeutic options and emerging drug resistance, necessitating the search for alternative therapeutic agents.

Our earlier studies have shown that Pentalinonsterol (Pen), isolated from Pentalinon andrieuxii plant, showed promising antileishmanial activities. However, the effects of Pen on the transcriptomic profile and nuclear factor erythroid 2-related factor 2 (Nrf-2) related alterations in host cells remain unclear.

The present study examines the impact of Pen on the transcriptomic profiles of human macrophages infected with Leishmania major, with a particular focus on its modulation of Nrf-2 pathway.

Bulk RNA-seq analysis revealed 1245 differentially expressed genes (DEGs), including 678 upregulated and 567 downregulated genes, using a significance threshold of log2 fold change ≥ 2 and a false discovery rate ≤ 0.05.

We found significant modulation of key cytokines, chemokines, and immune effector genes, including downregulation of IL-10, CXCL2, and CXCR3, and upregulation of TXN, GSR, SOD1, and CXCL8 indicating a selectively regulated inflammatory response. Pathway enrichment analysis demonstrated that Pen modified transcriptional profiles related to oxidative stress responses, validated by RT-PCR and confirmed by increased nuclear Nrf-2 translocation through biochemical and immunofluorescence assays.

These findings highlight Pen's potential as a dual action therapeutic, selectively modulating immune responses in favor of pathogen control while activating Nrf-2 driven antioxidant defenses to counteract oxidative stress. This integrated activity supports Pen's further advancement as a novel host directed therapeutic for leishmaniasis and other Nrf-2 associated inflammatory conditions.