P4HB/PDIA1: an emerging biomarker linking periprostatic adipose tissue and prostate cancer progression

Prolyl 4-hydroxylase subunit beta (P4HB), also known as protein disulfide isomerase A1 (PDIA1), is an endoplasmic reticulum oxidoreductase involved in protein folding, ER proteostasis, oxidative stress responses, collagen maturation, and extracellular matrix remodeling. Increasing evidence implicates P4HB in tumor progression and treatment resistance, although its role in the prostate cancer (PCa) microenvironment remains incompletely understood. Periprostatic adipose tissue (PPAT) is an active endocrine and paracrine compartment that undergoes metabolic remodeling during locally advanced PCa and participates in bidirectional communication with tumor cells through adipokines, cytokines, growth factors, extracellular matrix components, and metabolic mediators. Proteomic profiling of PPAT adjacent to pathological T3 tumors revealed enrichment of pathways involved in lipid mobilization and transport and identified P4HB within the PPAT secretome. Elevated tumoral P4HB expression has been associated with higher Gleason score, advanced disease stage, lymphovascular invasion, biochemical recurrence, residual disease, and radiotherapy resistance. Furthermore, experimental inhibition of PDI family proteins can suppress PCa growth, impair androgen receptor signaling, and enhance enzalutamide sensitivity. Collectively, these findings suggest that P4HB may link PPAT metabolic remodeling with aggressive PCa. PPAT-derived P4HB warrants further investigation as a biomarker and potential therapeutic target for microenvironment-directed treatment.