Objective: Prostate cancer (PCa) is the most common malignant tumor diagnosed in men in developed countries. In developing countries, the PCa morbidity and mortality rates are also increasing rapidly. Since androgen receptor (AR) is a key driver and plays a critical role in the regulation of PCa development, AR-targeted agents provide a key component of current therapy regimens. However, even new-generation AR antagonists are prone to drug resistance, and there is currently no effective strategy for overcoming advanced PCa aggressiveness, including drug-resistance progression. The aim of this study was to evaluate the potential efficacy and novel therapy strategy of proxalutamide (a newly developed AR antagonist) in PCa. Methods: Four PCa cell lines with various biological heterogeneities were utilized in this study, namely, androgen-sensitive/-insensitive with/without AR expression. Proliferation, migration and apoptosis assays in PCa cells were used to evaluate the effective therapeutic activity of proxalutamide. The changes in lipid droplet accumulation and lipidomic profiles were analyzed to determine the influence of proxalutamide on lipogenesis in PCa cells. The molecular basis of the effects of proxalutamide on lipogenesis and the AR axis was then further investigated. Results: Proxalutamide significantly inhibited the proliferation and migration of PCa cells, and its inhibitory effect was superior to that of enzalutamide (Enz, second-generation AR antagonist). Proxalutamide induced the caspase-dependent apoptosis of PCa cells. Proxalutamide significantly diminished the level of lipid droplets in PCa cells, changed the lipid profile of PCa cells and reduced the content of most lipids (especially triglycerides) in PCa cells. Proxalutamide attenuated de novo lipogenesis by inhibiting the expression of ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN) and sterol regulatory element-binding protein-1 (SREBP-1). Moreover, proxalutamide also decreased AR expression in PCa cells, and its inhibitory effect on lipogenesis did not depend on its ability to down-regulate AR expression. However, Enz had no effect on AR expression, lipid accumulation or lipid de novo synthesis in PCa cells. Conclusions: By co-targeting the AR axis and endogenous adipogenesis, a novel and promising strategy was established for proxalutamide to combat the progress of PCa. The unique effect of proxalutamide on the metabolic reprogramming of PCa provides a potential solution to overcome the resistance of current AR-targeted therapy, which will help to effectively prolong its clinical service life.

Background: Cisplatin-induced nephrotoxicity is a major dose-limiting complication of chemotherapy. However, effective protective strategies remain limited. Licochalcone A (LicoA), a flavonoid isolated from Glycyrrhiza inflata, exhibits multi-target bioactivity against oxidative stress, inflammation, and metabolic disorders. Methods: In vivo murine cisplatin-induced model and in vitro HK-2 cells were employed. HE/Masson staining, renal function, oxidative stress, ferroptosis markers (Fe ²⁺ , GSH, MDA, lipid peroxidation), and mitochondrial health were assessed. Mechanistic studies were conducted using metabolomic approaches, molecular docking, cellular thermal shift assay, Western blot, immunofluorescence, and Nrf2-knockdown assays. Results: LicoA significantly ameliorated cisplatin-induced renal dysfunction and attenuated the progression from acute kidney injury (AKI) to chronic kidney disease (CKD), as evidenced by reduced tubular injury and fibrosis. Metabolomic analysis revealed that LicoA restored energy metabolism and glutathione homeostasis. LicoA effectively alleviated cisplatin-induced ferroptosis by inhibiting Fe ²⁺ accumulation, reducing lipid peroxidation, restoring cellular redox homeostasis, and consequently diminishing membrane blistering. Molecular docking and cellular thermal shift assay confirmed the binding affinity between LicoA and both Nrf2 and GPX4. Crucially, Nrf2 knockdown abolished the protective effects of LicoA, demonstrating the essential role of the Nrf2 pathway. Conclusion: LicoA alleviated cisplatin-induced renal injury by activating the Nrf2/GPX4 axis, thereby suppressing ferroptosis and mitigating mitochondrial damage. These findings highlight the therapeutic potential of LicoA in preventing cisplatin nephrotoxicity and impeding the AKI-to-CKD transition.

[This corrects the article DOI: 10.3389/fphar.2026.1759824.].