Kumar Reetesh, Panda Siva Parsad, Abomughaid Mosleh Mohammad, Lakhanpal Sorabh, Avinash D, Jha Niraj Kumar, Gupta Rohan
Department of Bioengineering and Biotechnology, School of Biosciences & Technology, Galgotias University, Greater Noida, 203201, Uttar Pradesh, India.
Institute of Pharmaceutical Research, GLA University, Mathura, 281406, Uttar Pradesh, India.
Metab Brain Dis. 2025 Aug 29;40(7):251. doi: 10.1007/s11011-025-01685-9.
Neurodegenerative diseases (NDDs) are characterized by the progressive decline of neuronal structure and function, with neuroinflammation and neuronal death as key pathogenic features. Pyroptosis, a highly inflammatory kind of programmed cell death (PCD) facilitated by gasdermin (GSDM) proteins and inflammasome activation, has garnered significant attention among new mechanisms. The increased expression of pyroptosis-related proteins, frequently co-localized with misfolded protein aggregates, indicates a crucial involvement in the advancement of different NDDs. Further, microglial pyroptosis exacerbates neuronal damage by hindering the removal of neurotoxic chemicals and intensifying inflammatory responses. Epigenetic and post-translational modifications (PTMs) of histone and non-histone proteins, along with metabolic dysregulation, significantly influence pyroptotic signaling, ultimately expediting neurodegeneration. Pyroptosis, owing to its pivotal involvement in inflammation and neuronal demise, is gaining recognition as a possible diagnostic and prognostic biomarker, particularly in the advancement of immunotherapeutic approaches. Herein, we thoroughly examine the molecular control of pyroptosis through PTMs and metabolic pathways, its implications for neurodegenerative and neuropsychiatric disorders, and recent therapeutic developments aimed at targeting pyroptotic pathways. It emphasizes the advancement of novel diagnostic instruments, such as genetic reporters and nanomaterial-based molecular probes for the real-time and non-invasive identification of pyroptotic activity. These discoveries establish a foundation for future tailored treatment strategies designed to alleviate pyroptosis-induced neuroinflammation and neurodegeneration. HIGHLIGHTS: 1. Pyroptosis is a pro-inflammatory cell death linked to neuroinflammatory conditions. 2. ROS and oxidative stress connect pyroptosis with other cell death mechanisms. 3. Altered glucose and lipid metabolism influence pyroptosis and neuronal degeneration. 4. PTMs of GSDMD, caspase-1, and ASC regulate pyroptosis in brain disorders. 5. Targeting microglial pyroptosis offers potential therapy for neurodegenerative diseases.
神经退行性疾病（NDDs）的特征是神经元结构和功能的进行性衰退，神经炎症和神经元死亡是其关键的致病特征。细胞焦亡是一种由gasdermin（GSDM）蛋白和炎性小体激活介导的高度炎症性程序性细胞死亡（PCD），在新的机制中受到了广泛关注。细胞焦亡相关蛋白的表达增加，且常与错误折叠的蛋白聚集体共定位，表明其在不同神经退行性疾病的进展中起关键作用。此外，小胶质细胞焦亡通过阻碍神经毒性化学物质的清除和加剧炎症反应，加重神经元损伤。组蛋白和非组蛋白的表观遗传和翻译后修饰（PTMs）以及代谢失调，显著影响细胞焦亡信号通路，最终加速神经退行性变。由于细胞焦亡在炎症和神经元死亡中起关键作用，它正逐渐被视为一种可能的诊断和预后生物标志物，尤其是在免疫治疗方法的发展中。在此，我们全面研究了通过PTMs和代谢途径对细胞焦亡的分子调控，其对神经退行性和神经精神疾病的影响，以及针对细胞焦亡途径的最新治疗进展。它强调了新型诊断工具的发展，如用于实时和非侵入性识别细胞焦亡活性的基因报告器和基于纳米材料的分子探针。这些发现为未来旨在减轻细胞焦亡诱导的神经炎症和神经退行性变的定制治疗策略奠定了基础。要点：1. 细胞焦亡是一种与神经炎症状态相关的促炎性细胞死亡。2. 活性氧（ROS）和氧化应激将细胞焦亡与其他细胞死亡机制联系起来。3. 葡萄糖和脂质代谢的改变影响细胞焦亡和神经元变性。4. GSDMD、半胱天冬酶 -1和ASC的PTMs调节脑部疾病中的细胞焦亡。5. 靶向小胶质细胞焦亡为神经退行性疾病提供了潜在的治疗方法。
