A novel senolytic drug for pulmonary fibrosis: BTSA1 targets apoptosis of senescent myofibroblasts by activating BAX

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Aging Cell Pub Date : 2024-06-03 DOI:10.1111/acel.14229
Mengxia Shen, Jiafeng Fu, Yunna Zhang, Yanfen Chang, Xiaohong Li, Haipeng Cheng, Yujia Qiu, Min Shao, Yang Han, Yan Zhou, Ziqiang Luo
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Abstract

Idiopathic pulmonary fibrosis is a progressive and age-related disease that results from impaired lung repair following injury. Targeting senescent myofibroblasts with senolytic drugs attenuates pulmonary fibrosis, revealing a detrimental role of these cells in pulmonary fibrosis. The mechanisms underlying the occurrence and persistence of senescent myofibroblasts in fibrotic lung tissue require further clarification. In this study, we demonstrated that senescent myofibroblasts are resistant to apoptosis by upregulating the proapoptotic protein BAX and antiapoptotic protein BCL-2 and BCL-XL, leading to BAX inactivation. We further showed that high levels of inactive BAX-mediated minority mitochondrial outer membrane permeabilization (minority MOMP) promoted DNA damage and myofibroblasts senescence after insult by a sublethal stimulus. Intervention of minority MOMP via the inhibition of caspase activity by quinolyl-valyl-O-methylaspartyl-[2,6-difluorophenoxy]-methyl ketone (QVD-OPH) or BAX knockdown significantly reduced DNA damage and ultimately delayed the progression of senescence. Moreover, the BAX activator BTSA1 selectively promoted the apoptosis of senescent myofibroblasts, as BTSA1-activated BAX converted minority MOMP to complete MOMP while not injuring other cells with low levels of BAX. Furthermore, therapeutic activation of BAX with BTSA1 effectively reduced the number of senescent myofibroblasts in the lung tissue and alleviated both reversible and irreversible pulmonary fibrosis. These findings advance the understanding of apoptosis resistance and cellular senescence mechanisms in senescent myofibroblasts in pulmonary fibrosis and demonstrate a novel senolytic drug for pulmonary fibrosis treatment.

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治疗肺纤维化的新型衰老药物:BTSA1 通过激活 BAX 靶向衰老肌成纤维细胞的凋亡。
特发性肺纤维化是一种与年龄有关的渐进性疾病,是肺损伤后修复功能受损的结果。以衰老肌成纤维细胞为靶点的衰老药物可减轻肺纤维化,揭示了这些细胞在肺纤维化中的有害作用。衰老肌成纤维细胞在纤维化肺组织中的发生和持续存在的机制需要进一步阐明。在这项研究中,我们证实衰老肌成纤维细胞通过上调促凋亡蛋白 BAX 和抗凋亡蛋白 BCL-2 及 BCL-XL,导致 BAX 失活,从而抵抗细胞凋亡。我们进一步发现,高水平的非活性 BAX 介导的少数线粒体外膜通透(少数 MOMP)促进了 DNA 损伤和成肌细胞在受到亚致死刺激后的衰老。通过喹啉-缬氨酰-O-甲基天冬氨酰-[2,6-二氟苯氧基]-甲基酮(QVD-OPH)或敲除 BAX 来抑制 Caspase 的活性,可显著减少 DNA 损伤,并最终延缓衰老的进程。此外,BAX激活剂BTSA1可选择性地促进衰老肌成纤维细胞的凋亡,因为BTSA1激活的BAX可将少数澳门美高梅娱乐唯一官网转化为完全澳门美高梅娱乐唯一官网,而不会伤害其他低水平BAX的细胞。此外,用 BTSA1 治疗性激活 BAX 能有效减少肺组织中衰老肌成纤维细胞的数量,减轻可逆和不可逆的肺纤维化。这些发现加深了人们对肺纤维化中衰老肌成纤维细胞的凋亡抵抗和细胞衰老机制的认识,并证明了一种治疗肺纤维化的新型衰老溶解药物。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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