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

BACKGROUND

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.

PURPOSE: 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.

STUDY

DESIGN

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.