Metabolic Plasticity and Enzalutamide Resistance: Emerging Roles of PGK1 in Prostate Cancer

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ID: 314886
2026
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Abstract
Enzalutamide resistance remains a key challenge in the treatment of advanced prostate cancer (PCa), as clinical efficacy is frequently hindered by acquired resistance. While reactivation of AR signaling including AR splice variants, has been extensively studied, accumulating evidence indicates that metabolic reprogramming is a key adaptive response to sustained AR inhibition. As resistance advances, tumor cells exhibit metabolic plasticity, dynamically regulating glycolysis, mitochondrial respiration, lipid metabolism, and redox homeostasis to adapt to treatment pressure. In this context, phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme, has emerged as a potential mediator linking metabolic adaptation to therapy resistance. Beyond its ATP-generating function, PGK1 exhibits non-canonical functions, including regulation of mitochondrial metabolism, protein kinase activity, and stress-response signaling. These properties suggest that PGK1 may integrate AR-driven metabolic programs with downstream survival pathways under therapeutic pressure. Preclinical studies support a role for PGK1 in promoting glycolytic phenotypes and resistance-associated metabolic states. However, current evidence remains largely associative, and direct in vivo validation in prostate-specific models is limited. Moreover, whether PGK1 functions as a causal driver or downstream effector of resistance remains unresolved. This review summarizes current understanding of AR-metabolism coupling and evaluates PGK1 as a potential metabolic-signaling node in enzalutamide resistance, highlighting key knowledge gaps and future directions for metabolic targeting in PCa.
Reference Key
openalex_W7162302483 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Min Zhang, Xiaoqi Liu
Journal american journal of physiology endocrinology and metabolism
Year 2026
DOI
10.1210/endocr/bqag063
URL
Keywords Keywords not found

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