Fatty acid synthase (Fasn) inhibition improves hypertension-induced erectile dysfunction by suppressing oxidative stress and NLRP3 inflammasome-dependent pyroptosis through activating the Nrf2/HO-1 pathway

Background: Erectile dysfunction (ED) is a prevalent male sexual disorder, commonly associated with hypertension, though the underlying mechanisms remain poorly understood. Objective: This study aims to explore the role of Fatty acid synthase (Fasn) in hypertension-induced ED and evaluate the therapeutic potential of the Fasn inhibitor C75. Materials and Methods: Erectile function was assessed by determining the intracavernous pressure/ mean arterial pressure (ICP/MAP) ratio, followed by the collection of cavernous tissue for transcriptomic and non-targeted metabolomic analyses. In vitro, a concentration of 10-6 M angiotensin II (Ang II) was applied to rat aortic endothelial cells (RAOECs) to establish a model of hypertension. In vivo, spontaneously hypertensive rats (SHR) were randomly divided into two groups. The SHR+C75 group received intraperitoneal injections of C75 at a dose of 2 mg/kg once a week. After five weeks of treatment, the erectile function of the rats was assessed, and penile tissues were harvested for further analysis. Molecular and protein expression were assessed using Western blotting, qRT-PCR, immunofluorescence staining, and immunohistochemistry. Results: The SHR exhibited ED, indicated by reduced maximum ICP/MAP ratios. Histologically, corpus cavernosum tissue of SHR showed elevated fibrosis and endothelial dysfunction. Additionally, increased expression of the NLRP3 inflammasome, Caspase-1, GSDMD, and the pro-inflammatory cytokines IL-1β and IL-18 was observed. Multi-omics analysis revealed significant enrichment in lipid metabolic pathways, with Fasn identified as a hub gene. In vitro, siFasn and C75 enhanced antioxidant markers Nrf2 and HO-1, reduced ROS accumulation, and suppressed NLRP3 and GSDMD levels. In vivo, C75 treatment restored endothelial function and reversed erectile dysfunction, accompanied by decreased oxidative stress and pyroptosis in the penile corpus cavernosum. Conclusion: These findings suggest that Fasn inhibition may offer a promising therapeutic strategy for hypertension-induced ED by alleviating oxidative stress and suppressing NLRP3 inflammasome-dependent endothelial cell pyroptosis via activation of the Nrf2/HO-1 pathway.背景：勃起功能障碍（Erectile dysfunction, ED）是一种高发的男性性功能障碍，常与高血压存在关联，但其具体发病机制仍未完全阐明。 研究目的：本研究旨在探讨脂肪酸合酶（Fatty acid synthase, Fasn）在高血压诱导的勃起功能障碍中的作用，并评估脂肪酸合酶抑制剂C75的治疗潜力。 材料与方法：本研究通过测定海绵体内压/平均动脉压（intracavernous pressure/ mean arterial pressure, ICP/MAP）比值评估勃起功能，随后收集海绵体组织进行转录组学与非靶向代谢组学分析。体外实验中，采用浓度为10^-6 mol/L的血管紧张素II（angiotensin II, Ang II）处理大鼠主动脉内皮细胞（rat aortic endothelial cells, RAOECs）以构建高血压细胞模型。体内实验中，将自发性高血压大鼠（spontaneously hypertensive rats, SHR）随机分为两组；SHR+C75组每周一次腹腔注射2 mg/kg的C75。给药5周后，评估大鼠勃起功能，并收集阴茎组织用于后续实验分析。采用蛋白质印迹法（Western blotting）、实时定量聚合酶链式反应（qRT-PCR）、免疫荧光染色与免疫组织化学染色检测分子与蛋白表达水平。 研究结果：自发性高血压大鼠出现勃起功能障碍，表现为最大ICP/MAP比值降低。组织学分析显示，自发性高血压大鼠的阴茎海绵体组织纤维化程度升高且内皮功能受损。此外，研究观察到核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎症小体、半胱氨酸天冬氨酸蛋白酶-1（Caspase-1）、焦孔素D（GSDMD）以及促炎细胞因子白细胞介素1β（IL-1β）、白细胞介素18（IL-18）的表达水平均显著上调。多组学分析显示，脂质代谢通路显著富集，且Fasn被鉴定为核心枢纽基因。体外实验中，沉默Fasn（siFasn）与C75处理可上调抗氧化标志物核因子E2相关因子2（Nrf2）与血红素氧合酶1（HO-1）的表达，减少活性氧（reactive oxygen species, ROS）积累，并抑制NLRP3与GSDMD的表达水平。体内实验中，C75治疗可恢复内皮功能并逆转勃起功能障碍，同时伴随阴茎海绵体组织氧化应激与细胞焦亡水平降低。 结论：本研究结果表明，抑制Fasn可通过激活Nrf2/HO-1通路，减轻氧化应激并抑制NLRP3炎症小体依赖的内皮细胞焦亡，从而为高血压诱导的勃起功能障碍提供一种极具前景的治疗策略。