Targeting the feminized nature of prostate cancer exploring estrogen-driven metabolic reprogramming and its therapeutic intervention: A narrative review

Prostate cancer (PCa) has long been classified as an androgen-driven malignancy; however, mounting evidence underscores the pivotal role of estrogen in its initiation, progression, and therapeutic resistance. This review establishes that PCa exhibits intrinsic estrogen dependence through intratumoral aromatization, positioning it within the spectrum of estrogen-driven malignancies. Through integrative molecular analyses, we elucidate how estrogen orchestrates metabolic reprogramming, shifting prostate tumors toward enhanced lipid oxidation and glucose uptake a hallmark of glucolipotoxicity. Mechanistically, estrogen signaling, primarily via the PI3K/AKT pathway, drives the upregulation of carnitine palmitoyltransferase 1 and glucose transporter 1, fueling a metabolic storm characterized by oxidative stress, mitochondrial dysfunction, and chronic inflammatory signaling. This metabolic adaptation enables androgen-independent survival, presenting a critical vulnerability overlooked by conventional androgen-targeted therapies. Our findings necessitate a paradigm shift in the classification and treatment of PCa, advocating for a novel therapeutic framework targeting the estrogen–metabolic axis. We propose a precision strategy integrating aromatase inhibition, estrogen receptor blockade, and metabolic stress modulation to counteract castration-resistant disease. Recognizing PCa as an estrogen-driven, metabolically adaptive malignancy transforms its clinical understanding and therapeutic approach, demanding urgent reconsideration of current oncologic paradigms.