The developing role of NRF2 and HMOX1 in treatment response of cutaneous leishmaniasis

Anthroponotic cutaneous leishmaniasis (ACL), a neglected parasitic disease, created significant treatment challenges due to rising antimonial resistance, particularly in endemic regions like Iran. This study aimed to investigate the mechanisms behind treatment unresponsiveness in ACL patients. Demographic and clinical characteristics of 21 unresponsive and 10 responsive patients were randomly collected. Leishmania isolates were genotyped using nested polymerase chain reaction (PCR). Real-time PCR assessed the expression levels of two key genes related to treatment unresponsiveness: nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase 1 (HMOX1), along with their associated microRNAs, mir-24a-3p and mir-27b-3p. Gene expression and immunohistochemistry (IHC) assays measured apoptosis activation. Unresponsive patients revealed decreased expression of apoptosis-related genes (Bax, caspase-3, caspase-8) and increased expression of B-cell lymphoma 2 (Bcl2). Furthermore, HMOX1 and NRF2 expression, significant mir-27b-3p upregulation, and mir-24a-3p downregulation were observed in the unresponsive group. These results suggest diminished apoptosis and/or possible potential for chronic progression of Leishmania (L.) tropica infection in unresponsive patients. The increased levels of NRF2 and HMOX1 demonstrate their probable role in drug unresponsiveness. Also, the opposing effects of mir-24a-3p and mir-27b-3p on mentioned genes highlight the necessity for targeted molecular studies to modulate microRNAs expression effectively.