Inflammation-driven transcriptional reprogramming in prostate cancer: Convergence of NFκB, JAK/STAT3, and epigenetic remodeling in castration-resistant disease

Abstract

Chronic inflammation has emerged as a central driver for the initiation, progression, and therapeutic resistance of prostate cancer (CaP). While androgen receptor (AR) signaling serves as the primary axis for prostate tumorigenesis, mounting evidence suggests that continuous activation of inflammatory signaling pathways, especially nuclear factor kappa B (NFκB) and interleukin-6 (IL6)/Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathways, profoundly reshape the transcriptional and epigenetic landscape of advanced disease. These signaling pathways largely converge with AR signaling to form a common axis and promote tumor survival, proliferation, angiogenesis, immune evasion, epithelial to mesenchymal transition (EMT), and metastasis. Furthermore, prolonged exposure to cytokines such as IL6 and tumor necrosis factor-α (TNFα) leads to constitutive activation of STAT3 and NFκB signaling pathways. This persistent inflammatory signaling increases AR transcriptional activity even under androgen-deprived conditions, thereby facilitating the development of castration-resistant prostate cancer (CRPC). Apart from transcriptional crosstalk, inflammatory signaling pathways interact with epigenetic remodeling mechanisms, including histone modifications, DNA methylation, and dysregulation of chromatin modifiers such as EZH2, LSD1, and BRD4. These epigenetic variations stabilize aberrant gene expression programs and promote therapeutic resistance in metastatic CRPC. The present review discusses the crosstalk between inflammatory signaling, AR reprogramming, and epigenetic remodeling, and illustrates emerging therapeutic strategies targeting NFκB and JAK/STAT3 signaling pathways. This review highlights the importance of the integrated inflammatory-AR-epigenetic axis in CRPC progression and emphasizes its potential for improved biomarker stratification and the development of effective combinatorial therapeutic strategies to overcome resistance and improve clinical outcomes in advanced CaP.

Keywords: Androgen receptor (AR); Castration-resistant prostate cancer (CRPC); Epigenetic remodeling; Interleukin-6 (IL6); Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3); Nuclear factor kappa B (NFκB); Prostate cancer (CaP).