Ferroptosis and Nrf-2 signaling: a redox tug of war in leishmaniasis pathogenesis and host directed therapy.

Leishmaniasis is a neglected intracellular parasitic disease, where host response is shaped not only by Th1/Th2 immune polarization but also by iron availability, redox homeostasis and regulation of cell death pathways. Ferroptosis, a unique iron dependent cell death pathway has recently emerged as a critical mechanism in innate host protection against intracellular pathogens. In Leishmania infected macrophages, disruption of iron homeostasis and promotion of oxidative stress support an environment favorable for ferroptosis. However, parasites employ cytoprotective and antioxidant pathways, most importantly the nuclear factor erythroid 2-related factor (Nrf-2) signaling, to evade the ferroptosis mediated host response. Nrf-2 activates a wide array of antioxidant pathways, limiting ferroptosis and promoting parasites survival within macrophages. The balance between ferroptotic stress and Nrf-2 mediated antioxidant defense varies between cutaneous and visceral forms of leishmaniasis. In cutaneous leishmaniasis, early oxidative stress favors ferroptotic parasite control and transient Nrf-2 activation preserve tissue integrity, however sustained Nrf-2 activation suppresses ferroptosis and favors infection. In contrast, visceral leishmaniasis is characterized by systemic iron dysregulation and persistent Nrf-2 activation which creates a ferroptosis resistant environment. Targeting this context dependent ferroptosis/Nrf-2 axis offers a promising host directed strategy for leishmaniasis. Therapeutic approaches involving ferroptosis induction and Nrf-2 suppression may counteract ferroptosis resistance driven by antioxidant defenses and restore host antipathogen functions. This review integrates current insights into ferroptosis and Nrf-2 signaling in both cutaneous and visceral leishmaniasis. It further highlights potential therapeutic agents targeting ferroptosis and Nrf-2 pathways as promising candidates for host directed therapeutic strategies in leishmaniasis.