Post-translational modifications in prostate cancer: coordinated oncogenic networks and clinical implications

Prostate cancer (PCa) is one of the most prevalent malignancies affecting male health globally, ranking as the fifth leading cause of cancer-related mortality in men. Post-translational modifications (PTMs), encompassing a diverse array of biochemical alterations such as methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, glycosylation, and lactylation, constitute a critical category of epigenetic regulatory mechanisms that modulate numerous cellular processes in both physiological and pathological contexts. Despite their fundamental importance, the precise functional implications of PTMs in PCa pathogenesis remain incompletely elucidated. Current evidence has established that multiple oncogenic signaling pathways (including AR, PTEN/PI3K/AKT, CDK4/6-RB, Wnt/β-catenin, and JAK/STAT3), key transcription factors (such as AR, p53, ERG, NKX3.1, FOXA1, HOXB13, KLF, and MYC), and specific histone modification patterns are intimately associated with PCa progression. Furthermore, emerging studies have implicated PTMs in mediating drug resistance and immune suppression in PCa, representing two major clinical challenges in contemporary PCa management. Beyond these canonical regulatory mechanisms, metabolism-associated and emerging PTMs further connect metabolic reprogramming with AR variant splicing, lineage plasticity, immune modulation, and therapeutic resistance. We also discuss the clinical implications of PTMs in PCa, including PTM-directed clinical trials, targeted protein degradation strategies, and diagnostic or prognostic biomarker development. In light of these critical findings, this review systematically synthesizes current research elucidating the mechanistic roles of PTMs in regulating these molecular determinants of PCa progression, with the aim of providing a comprehensive understanding of PTM-mediated regulatory networks and offering translational insights for potential clinical applications.