Zhang Wangzheqi, Wu Huang, Liao Yan, Zhu Chenglong, Zou Zui
Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China; School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai 200433, China.
Basic Medical University, Naval Medical University, Shanghai 200433, China.
Autoimmun Rev. 2025 Jan 31;24(2):103714. doi: 10.1016/j.autrev.2024.103714. Epub 2024 Dec 3.
Programmed cell death (PCD) plays a crucial role in maintaining tissue homeostasis, with its primary forms including apoptosis, pyroptosis, and necroptosis. The caspase family is central to these processes, and its complex functions across different cell death pathways and other non-cell death roles have been closely linked to the pathogenesis of autoimmune diseases. This article provides a comprehensive review of the role of the caspase family in autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and multiple sclerosis (MS). It particularly emphasizes the intricate functions of caspases within various cell death pathways and their potential as therapeutic targets, thereby offering innovative insights and a thorough discussion in this field. In terms of therapy, strategies targeting caspases hold significant promise. We emphasize the importance of a holistic understanding of caspases in the overall concept of cell death, exploring their unique functions and interrelationships across multiple cell death pathways, including apoptosis, pyroptosis, necroptosis, and PANoptosis. This approach transcends the limitations of previous studies that focused on singular cell death pathways. Additionally, caspases play a key role in non-cell death functions, such as immune cell activation, cytokine processing, inflammation regulation, and tissue repair, thereby opening new avenues for the treatment of autoimmune diseases. Regulating caspase activity holds the potential to restore immune balance in autoimmune diseases. Potential therapeutic approaches include small molecule inhibitors (both reversible and irreversible), biological agents (such as monoclonal antibodies), and gene therapies. However, achieving specific modulation of caspases to avoid interference with normal physiological functions remains a major challenge. Future research must delve deeper into the regulatory mechanisms of caspases and their associated complexes linked to PANoptosis to facilitate precision medicine. In summary, this article offers a comprehensive and in-depth analysis, providing a novel perspective on the complex roles of caspases in autoimmune diseases, with the potential to catalyze breakthroughs in understanding disease mechanisms and developing therapeutic strategies.
程序性细胞死亡（PCD）在维持组织稳态中起着至关重要的作用，其主要形式包括凋亡、焦亡和坏死性凋亡。半胱天冬酶家族是这些过程的核心，其在不同细胞死亡途径中的复杂功能以及其他非细胞死亡作用与自身免疫性疾病的发病机制密切相关。本文全面综述了半胱天冬酶家族在类风湿关节炎（RA）、系统性红斑狼疮（SLE）、1型糖尿病（T1D）和多发性硬化症（MS）等自身免疫性疾病中的作用。特别强调了半胱天冬酶在各种细胞死亡途径中的复杂功能及其作为治疗靶点的潜力，从而在该领域提供了创新见解和深入讨论。在治疗方面，靶向半胱天冬酶的策略具有重大前景。我们强调在细胞死亡的整体概念中全面理解半胱天冬酶的重要性，探索它们在包括凋亡、焦亡、坏死性凋亡和PANoptosis在内的多种细胞死亡途径中的独特功能和相互关系。这种方法超越了以往专注于单一细胞死亡途径的研究的局限性。此外，半胱天冬酶在非细胞死亡功能中起关键作用，如免疫细胞激活、细胞因子加工、炎症调节和组织修复，从而为自身免疫性疾病的治疗开辟了新途径。调节半胱天冬酶活性有可能恢复自身免疫性疾病中的免疫平衡。潜在的治疗方法包括小分子抑制剂（可逆和不可逆）、生物制剂（如单克隆抗体）和基因疗法。然而，实现对半胱天冬酶的特异性调节以避免干扰正常生理功能仍然是一个重大挑战。未来的研究必须更深入地探究半胱天冬酶及其与PANoptosis相关复合物的调节机制，以促进精准医学。总之，本文提供了全面而深入的分析，为半胱天冬酶在自身免疫性疾病中的复杂作用提供了新视角，有可能推动在理解疾病机制和开发治疗策略方面取得突破。
