Hydroxycitric acid inhibits ferroptosis and ameliorates benign prostatic hyperplasia by upregulating the Nrf2/GPX4 pathway.

PURPOSE: Benign prostatic hyperplasia (BPH) poses a significant public health challenge, affecting a substantial portion of aging men worldwide. Current therapeutic options offer limited efficacy. The pathogenesis of BPH is multifactorial, involving ferroptosis, oxidative stress, and chronic inflammation. Hydroxycitric acid (HCA) is a natural compound with diverse pharmacological activities, including the inhibition of ferroptosis, anti-inflammatory, anti-oxidative stress, and anti-tumor effects. However, its role in BPH remains unexplored. This study aimed to investigate the effects of HCA on BPH and elucidate the underlying mechanisms, with the goal of providing novel therapeutic insights for BPH treatment. METHODS: C57BL/6J mice were used to establish a BPH model induced by testosterone propionate (TP). Animals were then randomly assigned to the following groups: Sham, BPH, BPH + Lip-1, BPH + Bru, BPH + HCA + Bru, and BPH + HCA. Prostate index (PI) was determined, and histopathological changes were evaluated by hematoxylin and eosin (HE) staining. Mitochondrial morphology was analyzed by TEM. The levels of Fe(2+), MDA, and GSH in prostate tissues were measured. Western blot analysis was performed to assess the protein expression of Nrf2 and GPX4. RESULTS: Compared to the Sham group, the prostate tissues of the BPH group exhibited typical histopathological features of hyperplasia, including epithelial cell proliferation, increased glandular lumen size. Concurrently, the levels of ferroptosis markers Fe(2+) (P < 0.01) and MDA (P < 0.001) were significantly elevated, while the expression of GSH (P < 0.01) and GPX4 (P < 0.05) was downregulated. Furthermore, mitochondrial morphology showed abnormalities. HCA treatment significantly reduced PI (P < 0.01) and attenuated epithelial cell proliferation and glandular lumen enlargement (P < 0.01, P < 0.001, respectively). HCA also reduced the levels of Fe(2+) (P < 0.05) and MDA (P < 0.05), and elevated GSH levels (P < 0.01). Furthermore, HCA upregulated the expression of Nrf2 (P < 0.01) and GPX4 (P < 0.01). The Nrf2 inhibitor Brusatol increased the levels of Fe(2+) (P < 0.05) and MDA (P < 0.05), and downregulated the expression of Nrf2 (P < 0.05) and GPX4 (P < 0.05), thereby attenuating the protective effects of HCA. However, co-administration of HCA and Brusatol partially reversed changes in Fe(2+) (P < 0.05) and MDA (P < 0.05) levels, and increased the expression of Nrf2 (P < 0.05) and GPX4 (P < 0.05), indicating reduction in Brusatol-induced effects. Furthermore, HCA treatment did not significantly affect liver and kidney function markers (AST, ALT, SCR, and UR) (P > 0.05). CONCLUSION: HCA inhibits ferroptosis by activating the Nrf2/GPX4 pathway, thereby ameliorating the pathological changes in BPH induced by TP. This study suggests a novel therapeutic strategy for BPH.