Molecular Mechanisms of Cell Death in <i>Leishmania donovani</i> Induced by Selected Steroidal Alkaloids

We have earlier reported novel anti-leishmanial molecules, veratramine and hupehenine, targeting dephospho-coenzyme A kinase of the parasite. In our current investigation, we assessed the efficacy of these two steroidal alkaloids, veratramine and hupehenine, in combating the parasite. Contrary to expectations, our study did not detect the typical signs of apoptosis such as mitochondrial membrane potential loss and phosphatidylserine externalization. Instead, we observed a notable increase in acidic organelle formation, suggesting a pro-survival response in promastigotes. Through diverse flow cytometric analyses and imaging methods, we conclude that the parasitic death induced by these natural compounds does not follow the apoptosis pathway but likely involves autophagy. This discovery marks the first instance of autophagy-mediated cell death in Leishmania donovani triggered by veratramine and hupehenine.