Bisphenol A promotes prostatic inflammatory susceptibility via PI3K/AKT-mediated mitochondrial stress and NLRP3 inflammasome sensitization.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a frequently encountered and distressing disorder of the urinary system, yet the contribution of ubiquitous environmental contaminants such as bisphenol A (BPA) remains poorly understood. In this study, we integrated network toxicology, molecular docking and molecular dynamics simulations, and experimental validation to investigate this association. In RWPE-1 cells, BPA pretreatment markedly enhanced subsequent lipopolysaccharide (LPS)-induced inflammatory responses, indicating that BPA acts not as a potent direct pro-inflammatory stimulus, but rather as a sensitizer that lowers the threshold for inflammatory activation. Network toxicology, followed by molecular docking and molecular dynamics simulations, identified the PI3K/AKT signaling pathway as a potential target of BPA, with AKT1 emerging as a key candidate that exhibited stable binding in silico. This mechanism was further validated both in vitro and in vivo, where BPA exposure was associated with suppression of PI3K/AKT signaling, exacerbation of mitochondrial oxidative stress, accumulation of oxidized mitochondrial DNA, and enhanced activation of the NLRP3 inflammasome, as evidenced by increased levels of NLRP3, ASC, cleaved caspase-1, and mature IL-1β. Functionally, activation of PI3K/AKT by SC79 significantly attenuated BPA-induced oxidative stress, mitochondrial dysfunction, and inflammasome activation, whereas the mitochondrial reactive oxygen species scavenger Mito-TEMPO primarily inhibited downstream inflammasome activation. In an experimental autoimmune prostatitis model, BPA exposure exacerbated prostatic inflammation and inflammatory cytokine production, effects that were markedly reversed by SC79 and Mito-TEMPO. Collectively, our study provides integrative evidence that environmental BPA exposure may contribute to increased susceptibility to prostatic inflammation under pathological conditions and identifies impaired PI3K/AKT signaling, mitochondrial oxidative stress, and NLRP3 inflammasome activation as key underlying mechanisms, thereby providing a mechanistic basis for future preventive and therapeutic strategies.