Imperatorin induces ferroptosis via mediating lipid peroxidation and SLC7A11/ACSL4/GPX4 signaling for inhibition and therapeutics of prostate cancer.

Prostate cancer (PCa) remains a leading cause of cancer-related death among males worldwide. Targeting ferroptosis has now emerged as a promising strategy against cancer. This study aims to deciphering the anti-tumor role of imperatorin, a natural furanocoumarin, in mediating ferroptosis-induced mechanisms for PCa inhibition and treatment. Cell-based assays, including CCK-8, EdU, colony formation, migration, and invasion assays, were used to evaluate the effects of imperatorin on cellular malignant phenotypes. RNA sequencing and bioinformatics analyses identified ferroptosis-related marker signatures, i.e., SLC7A11, ACSL4 and GPX4, were key targets of imperatorin, which were functionally validated using experimental approaches to establish its binding role of ferroptosis, clarify drug specificity, and support translational relevance. It is showed that imperatorin inhibited proliferation, migration, and invasion of PCa cells in a dose-dependent manner by triggering ferroptosis with a potential mechanism of inducing lipid peroxidation via downregulating SLC7A11/GPX4 and upregulating ACSL4. In particular, a significant decreased level of TRIM21-mediated ubiquitination was detected in ACSL4 after imperatorin treatment. Moreover, imperatorin exhibited a synergistic effect with Enzalutamide in vitro, highlighting it as a latent medication strategy for combination therapy. In vivo characterization further demonstrated that imperatorin reduced tumor growth and altered the expression of ferroptosis marker signatures with favorable safety on vital organs from toxicity. This study revealed the ferroptosis-induced power of imperatorin, indicating it as a novel therapeutic candidate against PCa resistance. Future pharmacological and clinical analyses will be conducted for translational understanding of the findings to personalized PCa management.