泛凋亡在心血管疾病中的作用与干预策略

Roles and intervention strategies of PANoptosis in cardiovascular diseases

摘要

心血管疾病长期位居全球死因首位，心血管疾病的病理过程往往伴随心肌细胞死亡，其中焦亡、凋亡与坏死性凋亡发挥了关键作用。然而，传统对单一死亡方式的研究难以阐明心血管损伤中多通路同步激活与交叉调控的复杂病理全貌。泛凋亡（PANoptosis）是一种通过泛凋亡小体（PANoptosome）复合物将焦亡、凋亡、坏死性凋亡整合于相同分子平台，进而实现统一调控的协同性细胞死亡模式，能够全面反映心血管损伤中细胞死亡的调控网络。不同的心血管疾病依赖的PANoptosome不同，同种疾病的不同阶段也具有差异性，体现了心血管疾病中PANoptosis的特异性和时空性。复杂的多节点调控网络也使得多靶点抑制剂、天然产物、中药复方及老药新用等干预策略在临床转化上有了一席之地。本综述探讨了7类心血管疾病中PANoptosis的作用机制、调控网络与干预方式，并结合PANoptosome分子亚型与疾病病程分期的双重特征加以论述。此外，表观遗传修饰、非编码RNA等新兴维度下PANoptosis的协同机制及其发展前景，也为心血管疾病的干预提供了新思路。因此，基于PANoptosome亚型分型建立的精准干预框架，有助于推动心血管疾病的个性化治疗，开拓了心血管疾病治疗的新视野。

Abstract

Cardiovascular diseases have long ranked first among global causes of death, and their pathological processes are frequently accompanied by cardiomyocyte death, in which pyroptosis, apoptosis and necroptosis play pivotal roles. However, traditional studies of individual cell death modalities are insufficient to fully characterize the complex pathological landscape of synchronous activation and crosstalk among multiple death pathways in cardiovascular injury. PANoptosis, a synergistic cell death modality that integrates pyroptosis, apoptosis, and necroptosis on the same molecular platform through the PANoptosome complex for unified regulation, comprehensively reflects the cell death regulatory network underlying cardiovascular injury. Different cardiovascular diseases depend on distinct PANoptosomes, and different stages of the same disease likewise display divergence, underscoring the disease-specific and spatiotemporal nature of PANoptosis in cardiovascular disease. This complex multi-nodal regulatory network has also enabled multi-target inhibitors, natural products and traditional Chinese medicine formulas, as well as drug repurposing, to gain a foothold in clinical translation. In this review, we discuss the mechanisms, regulatory networks, and therapeutic approaches targeting PANoptosis across seven categories of cardiovascular diseases, with particular emphasis on the dual features of PANoptosome molecular subtypes and disease stages. Furthermore, the synergistic mechanisms of PANoptosis from emerging perspectives, including epigenetic modifications and non-coding RNAs, together with their future prospects, provide novel insights into interventions for cardiovascular diseases. Accordingly, the precision intervention framework established based on PANoptosome subtyping can facilitate personalized therapy for cardiovascular diseases and open new horizons for their treatment.

关键词

泛凋亡 / 泛凋亡小体 / 心血管疾病 / 细胞死亡 / 多靶点抑制剂 / 精准干预

Key words

PANoptosis / PANoptosome / Cardiovascular diseases / Cell death / Multi-target inhibitors / Precision intervention

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基金资助

国家自然科学基金面上项目(82572494)