Luo Yanfang, Long Muyang, Wu Xueqin, Zeng Liuting
Department of Nephrology, The Central Hospital of Shaoyang, Shaoyang, Hunan, China.
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
Front Immunol. 2025 Nov 20;16:1703560. doi: 10.3389/fimmu.2025.1703560. eCollection 2025.
Inflammatory responses represent a core pathological process driving the progression of both acute and chronic kidney diseases. As a key effector of the innate immune system, the NLRP3 inflammasome is widely activated in renal resident cellsand infiltrating immune cells, positioning it as a critical nexus linking metabolic dysregulation, cellular stress, and tissue injury. Accumulating preclinical and clinical evidence in recent years demonstrates that aberrant activation of the NLRP3 inflammasome directly promotes glomerular damage, tubulointerstitial inflammation, fibrosis, and vascular dysfunction through the release of IL-1β and IL-18 and the induction of pyroptosis, thereby contributing to the pathogenesis of diverse renal disorders including acute kidney injury (AKI), diabetic kidney disease (DKD), IgA nephropathy, lupus nephritis, and chronic renal fibrosis. This review systematically delineates the multilayered regulatory mechanisms of the NLRP3 inflammasome within the renal microenvironment-including upstream activating signals, downstream effector pathways, and crosstalk with autophagy, mitochondrial dynamics, and epigenetic regulation. We particularly focus on how disease-specific triggers in kidney pathologies such as hyperglycemia, uric acid, lipotoxicity, and ischemia reperfusion instrumentalize NLRP3 to drive irreversible renal injury. Critically, we provide a comprehensive evaluation of current advances in the development of small-molecule inhibitors targeting the NLRP3 inflammasome pathway, encompassing preclinical and clinical trial data for agents that directly modulate NLRP3 protein conformation, inhibit ASC oligomerization, block caspase-1 activity, or neutralize IL-1β. We further dissect the differential therapeutic efficacy, tissue selectivity, safety margins, and emerging resistance mechanisms of these inhibitors across distinct renal disease models, while highlighting key translational challenges-including the lack of validated biomarkers, difficulties in patient stratification, and inefficient renal-targeted drug delivery. This review aims to establish a systematic theoretical framework for mechanistic research into renal inflammatory diseases and to provide a target rationale and a clinical development roadmap for the design of next-generation precision anti-inflammatory therapies, thereby accelerating the translation of NLRP3-targeted interventions from bench to bedside for patients with kidney disease.
炎症反应是驱动急性和慢性肾脏疾病进展的核心病理过程。作为固有免疫系统的关键效应器，NLRP3炎性小体在肾脏固有细胞和浸润的免疫细胞中广泛激活，使其成为连接代谢失调、细胞应激和组织损伤的关键枢纽。近年来，越来越多的临床前和临床证据表明，NLRP3炎性小体的异常激活通过释放IL-1β和IL-18以及诱导细胞焦亡，直接促进肾小球损伤、肾小管间质炎症、纤维化和血管功能障碍，从而导致包括急性肾损伤（AKI）、糖尿病肾病（DKD）、IgA肾病、狼疮性肾炎和慢性肾纤维化在内的多种肾脏疾病的发病机制。本综述系统地阐述了肾脏微环境中NLRP3炎性小体的多层调节机制，包括上游激活信号、下游效应途径以及与自噬、线粒体动力学和表观遗传调控的相互作用。我们特别关注肾脏疾病中特定疾病触发因素，如高血糖、尿酸、脂毒性和缺血再灌注如何利用NLRP3驱动不可逆的肾损伤。至关重要的是，我们全面评估了靶向NLRP3炎性小体途径的小分子抑制剂开发的当前进展，包括直接调节NLRP3蛋白构象、抑制ASC寡聚化、阻断caspase-1活性或中和IL-1β的药物的临床前和临床试验数据。我们进一步剖析了这些抑制剂在不同肾脏疾病模型中的差异治疗效果、组织选择性、安全范围和新出现的耐药机制，同时强调了关键的转化挑战，包括缺乏经过验证的生物标志物、患者分层困难以及肾脏靶向药物递送效率低下。本综述旨在为肾脏炎症性疾病的机制研究建立一个系统的理论框架，并为下一代精准抗炎疗法的设计提供靶点依据和临床开发路线图，从而加速针对肾病患者的NLRP3靶向干预从 bench到 bedside的转化。
