Unveiling the dark side of Moringa: High doses of Moringa oleifera Lam. Leaf extract increase the risk of adenocarcinoma in obesity-induced prostate hyperplasia through hyperhomocysteinemia/miR-155/STAT3 cascade.

Ethnopharmacological relevance: Moringa oleifera Lam., known as the "miracle tree", has been applauded as a complementary medicine, owing to its broad-spectrum health benefits.

Aim: This study provides novel insights into the unrecognized risk associated with the use of high-dose M. oleifera Lam. leaf extract (MLE) in an obesity-induced prostate hyperplasia (BPH) rat model.

Methods: Dry M. oleifera leaves were water-extracted, and the phytocomposition was determined using HPLC and GC-MS. Obesity-related BPH symptoms were induced in male Sprague Dawley rats receiving a high-fat diet (HFD) for 12 weeks, plus testosterone propionate injected subcutaneously (10 mg/kg/day in corn oil) for 4 weeks. BPH animals received different MLE doses, a reference drug (Prostride), and a combination of MLE + Prostride for 30 days. The therapeutic efficacy of different treatments was assessed in terms of their modulatory effect on obesity-related markers, including body weight, lipid profile, plasma homocysteine (Hcy), and BPH-related markers, including prostate index, androgenic hormones, and prostatic transcriptome of inflammatory/oncogenic/apoptotic mediators.

Results: the MLE treatment presented a dose-dependent effect in BPH animals, where the low and medium doses alleviated the BPH symptoms, as indicated by the restoration of redox homeostasis and nearly normalizing the inflammatory, oncogenic, and apoptotic transcriptome in treated prostates, reflected by the reversal of histopathological alterations. Conversely, the high-dose MLE aggravated BPH symptoms and further promoted a protumorigenic milieu through elevating plasma Hcy, which simultaneously upregulated a miR-155/STAT3-mediated oncogenic cascade.

Conclusion: These findings emphasize the need for cautious dose optimization in future translational applications of MLE and reinforce the importance of context-specific phytotherapy.