Fan Zongyao, Ge Qingyu, Ni Bin, Zhang Junjie, Du Tianpeng, Xu Hewei, Duan Zheng, Zhang Sicong, Wang Chao, Xue Jun, Ling Feng, Chen Zhengsen, Shen Baixin, Wei Zhongqing
Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, People's Republic of China.
Department of Urology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200000, People's Republic of China.
J Inflamm Res. 2025 Aug 24;18:11577-11592. doi: 10.2147/JIR.S545880. eCollection 2025.
Interstitial cystitis/bladder pain syndrome (IC/BPS) has become a pressing clinical issue due to its unclear etiology and severe, persistent pelvic pain. Despite extensive research, the pathogenesis of IC/BPS remains unresolved, and current treatments primarily target symptom relief rather than addressing underlying disease mechanisms. This study aimed to investigate the effects of nuclear factor erythroid 2-related factor 2 (NRF2) on IC/BPS and the potential molecular mechanisms.
Bladder mucosal biopsies from IC/BPS patients were subjected to RT-qPCR and immunoblotting to quantify NRF2 mRNA/protein expression. In vivo modeling, WT and NRF2 gene knockout mice received intraperitoneal cyclophosphamide to induce cystitis. Bladder function was assessed via Void Spot Assays, and Urodynamic. In vitro validation, LPS-stimulated SV-HUC-1 cells were transduced with NRF2 knockdown or overexpression, and oxidative stress and inflammation levels were evaluated. Then, the molecular mechanism of NRF2 in IC/BPS was determined by conducting Western blot, mass spectrometry, co-immunoprecipitation, and RT-qPCR analyses.
This study identified markedly reduced expression of NRF2 in the lesional bladder mucosa of patients with IC/BPS. By employing NRF2 knockout mice and cellular models of bladder inflammation, the essential role of NRF2 in modulating oxidative stress and inflammation was underscored. Furthermore, tripartite motif-containing 21 (TRIM21) interacted with NRF2, promoting its degradation via ubiquitination in bladder epithelial cell lines, thus elucidating TRIM21's regulatory role in bladder inflammation. Additionally, N6-methyladenosine (M6A) modifications recognized by IGF2BP2 enhanced TRIM21 expression by stabilizing TRIM21 mRNA.
This study positions the TRIM21-NRF2 axis as a key regulator of oxidative stress and inflammation in IC/BPS and suggests it as a promising therapeutic target for future IC/BPS interventions.
间质性膀胱炎/膀胱疼痛综合征（IC/BPS）因其病因不明以及严重、持续的盆腔疼痛，已成为一个紧迫的临床问题。尽管进行了广泛研究，IC/BPS的发病机制仍未解决，目前的治疗主要针对症状缓解，而非解决潜在的疾病机制。本研究旨在探讨核因子红细胞2相关因子2（NRF2）对IC/BPS的影响及其潜在分子机制。
对IC/BPS患者的膀胱黏膜活检组织进行逆转录定量聚合酶链反应（RT-qPCR）和免疫印迹分析，以量化NRF2信使核糖核酸（mRNA）/蛋白表达。在体内建模中，野生型（WT）和NRF2基因敲除小鼠腹腔注射环磷酰胺以诱导膀胱炎。通过排尿点试验和尿动力学评估膀胱功能。在体外验证中，用NRF2敲低或过表达转导脂多糖（LPS）刺激的人膀胱上皮永生化细胞系（SV-HUC-1），并评估氧化应激和炎症水平。然后，通过蛋白质免疫印迹、质谱分析、免疫共沉淀和RT-qPCR分析确定NRF2在IC/BPS中的分子机制。
本研究发现IC/BPS患者病变膀胱黏膜中NRF2表达显著降低。通过使用NRF2基因敲除小鼠和膀胱炎症细胞模型，强调了NRF2在调节氧化应激和炎症中的重要作用。此外，含三联基序蛋白21（TRIM21）与NRF交互作用，通过在膀胱上皮细胞系中泛素化促进其降解，从而阐明TRIM21在膀胱炎症中的调节作用。此外，胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）识别的N6-甲基腺苷（M6A）修饰通过稳定TRIM21 mRNA增强了TRIM21表达。
本研究将TRIM21-NRF2轴定位为IC/BPS中氧化应激和炎症的关键调节因子，并表明其作为未来IC/BPS干预的有前景的治疗靶点。
