Shi Jintao, Xuan Yang, Zhang Qinyu, Chen Jiangtao, Zhu Weihan, Zhang Hao, Duan Yue
The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China.
Department of Urology and Andrology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, People's Republic of China.
J Inflamm Res. 2025 Jul 29;18:10061-10079. doi: 10.2147/JIR.S527722. eCollection 2025.
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), a chronic inflammatory disorder with complex etiology and limited treatment options, is closely associated with oxidative stress and regulates cell death. Ferroptosis-an iron-dependent cell death driven by lipid peroxidation-amplifies CP/CPPS inflammation by concurrently triggering mitochondrial apoptosis and NLRP3 inflammasome activation, while Keap1/Nrf2/HO-1 axis serves as a central regulator bridging ferroptotic, apoptotic, and inflammatory cell death pathways. Astragaloside IV (AS-IV), a primary bioactive component of Astragalus membranaceus with established clinical use in urological therapies and favorable pharmacokinetics, was prioritized over structural analogs due to its unique dual-phase modulation: enhancing Nrf2 nuclear translocation without suppressing NF-κB-mediated immune surveillance. However, regulatory mechanisms linking AS-IV to ferroptosis inhibition in CP/CPPS remain unknown.
This study aimed to investigate the therapeutic potential of astragaloside IV (the primary bioactive component of ) for the treatment of CP/CPPS by suppressing ferroptosis via the Keap1/Nrf2/HO-1 pathway. A rat CP/CPPS model was established using complete Freund's adjuvant (CFA), with animals divided into normal control, EAP, and AS-IV high/medium/low-dose groups and treated daily for four weeks. Additionally, a human prostatic epithelial cell (RWPE-1) inflammation model was induced by lipopolysaccharide (LPS), and cells were categorized into control, LPS, AS-IV medium-dose, ferroptosis inhibitor, and Nrf2 inhibitor + AS-IV medium-dose groups.
AS-IV ameliorated prostatic tissue inflammation and fibrosis, reduced lipid peroxidation marker malondialdehyde (MDA) levels, and enhanced antioxidant indicators, including glutathione (GSH) content and glutathione peroxidase 4 (GPX4) activity. Western blotting and immunohistochemical analyses further confirmed that AS-IV activated the antioxidant pathway by suppressing Keap1 expression, promoting Nrf2 nuclear translocation, and upregulating heme oxygenase-1 (HO-1) protein levels. Concurrently, pro-inflammatory cytokine levels, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were markedly reduced.
This is the first study to demonstrate that AS-IV alleviates type III CP pathological damage by inhibiting ferroptosis via the Keap1/Nrf2/HO-1 axis, thereby providing experimental evidence for the development of multi-target therapeutic strategies based on natural products.
慢性前列腺炎/慢性盆腔疼痛综合征（CP/CPPS）是一种病因复杂、治疗选择有限的慢性炎症性疾病，与氧化应激密切相关并调节细胞死亡。铁死亡——一种由脂质过氧化驱动的铁依赖性细胞死亡——通过同时触发线粒体凋亡和NLRP3炎性小体激活来放大CP/CPPS炎症，而Keap1/Nrf2/HO-1轴作为连接铁死亡、凋亡和炎性细胞死亡途径的核心调节因子。黄芪甲苷（AS-IV）是黄芪的主要生物活性成分，在泌尿外科治疗中具有既定的临床应用且药代动力学良好，由于其独特的双相调节作用：增强Nrf2核转位而不抑制NF-κB介导的免疫监视，因此在结构类似物中被优先考虑。然而，AS-IV与CP/CPPS中铁死亡抑制之间的调控机制尚不清楚。
本研究旨在通过Keap1/Nrf2/HO-1途径抑制铁死亡来研究黄芪甲苷（黄芪的主要生物活性成分）治疗CP/CPPS的潜在疗效。使用完全弗氏佐剂（CFA）建立大鼠CP/CPPS模型，将动物分为正常对照组、EAP组和AS-IV高/中/低剂量组，并每天给药四周。此外，用脂多糖（LPS）诱导人前列腺上皮细胞（RWPE-1）炎症模型，并将细胞分为对照组、LPS组、AS-IV中剂量组、铁死亡抑制剂组和Nrf2抑制剂+AS-IV中剂量组。
AS-IV改善了前列腺组织炎症和纤维化，降低了脂质过氧化标志物丙二醛（MDA）水平，并增强了抗氧化指标，包括谷胱甘肽（GSH）含量和谷胱甘肽过氧化物酶4（GPX4）活性。蛋白质印迹和免疫组织化学分析进一步证实，AS-IV通过抑制Keap1表达、促进Nrf2核转位和上调血红素加氧酶-1（HO-1）蛋白来激活抗氧化途径。同时，促炎细胞因子水平，包括肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6），显著降低。
本研究首次证明AS-IV通过Keap1/Nrf2/HO-1轴抑制铁死亡来减轻III型CP的病理损伤，从而为基于天然产物的多靶点治疗策略的开发提供实验证据。
