N-acetylcysteine alleviates experimental autoimmune prostatitis in rats by activating PI3K/Akt/CREB and Keap1/Nrf2 pathways.

Background: The pathogenesis of non-bacterial chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) remains incompletely understood. Aberrant autoimmune responses have emerged as a prominent hypothetical contributor to CP/CPPS development. N-acetylcysteine (NAC), a well-established antioxidant agent, has demonstrated therapeutic efficacy in multiple disease models. This study aimed to systematically investigate the protective effects of NAC in experimental autoimmune prostatitis (EAP) rat models, with parallel exploration of its molecular mechanisms. Methods: Prostate tissues from ten rats were prepared as antigen to the establish EAP rat model. Twenty-four rats were randomly assigned to three groups: control (CON), EAP, and EAP + NAC. After 4 weeks of NAC treatment, mechanical allodynia was assessed using von-Frey filaments. Western blot, enzyme linked immunosorbent assay and immunohistochemistry were used to measure molecular expression. Hematoxylin-eosin and immunofluorescence staining were used to visualize inflammatory infiltration. Results: Compared to the CON and EAP + NAC groups, the EAP group showed significantly increased mechanical allodynia, along with markedly higher levels of inflammatory markers and oxidative stress. Further mechanistic studies revealed that both the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/cAMP-response element binding protein (CREB) signaling axis and the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway were substantially more activated in the CON and EAP+NAC groups than in the untreated EAP rats. Conclusions: This study demonstrated that NAC could effectively ameliorate CP/CPPS by specifically activating the PI3K/Akt/CREB and Keap1/Nrf2 pathways.