Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, PR China.
Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, PR China; Key Laboratory of Genetic Evolution & Animal Models,Chinese Academy of Sciences, Kunming 650201, PR China; University of Chinese Academy of Sciences, Beijing 101408, PR China.
Phytomedicine. 2024 Oct;133:155882. doi: 10.1016/j.phymed.2024.155882. Epub 2024 Jul 27.
Treating Idiopathic pulmonary fibrosis (IPF) remains challenging owing to its relentless progression, grim prognosis, and the scarcity of effective treatment options. Emerging evidence strongly supports the critical role of accelerated senescence in alveolar epithelial cells (AECs) in driving the progression of IPF. Consequently, targeting senescent AECs emerges as a promising therapeutic strategy for IPF.
Curcumin analogue EF24 is a derivative of curcumin and shows heightened bioactivity encompassing anti-inflammatory, anti-tumor and anti-aging properties. The objective of this study was to elucidate the therapeutic potential and underlying molecular mechanisms of EF24 in the treatment of IPF.
A549 and ATII cells were induced to become senescent using bleomycin. Senescence markers were examined using different methods including senescence-associated β-galactosidase (SA-β-gal) staining, western blotting, and q-PCR. Mice were intratracheally administrated with bleomycin to induce pulmonary fibrosis. This was validated by micro-computed tomography (CT), masson trichrome staining, and transmission electron microscope (TEM). The role and underlying mechanisms of EF24 in IPF were determined in vitro and in vivo by evaluating the expressions of PTEN, AKT/mTOR/NF-κB signaling pathway, and mitophagy using western blotting or flow cytometry.
We identified that the curcumin analogue EF24 was the most promising candidate among 12 compounds against IPF. EF24 treatment significantly reduced senescence biomarkers in bleomycin-induced senescent AECs, including SA-β-Gal, PAI-1, P21, and the senescence-associated secretory phenotype (SASP). EF24 also effectively inhibited fibroblast activation which was induced by senescent AECs or TGF-β. We revealed that PTEN activation was integral for EF24 to inhibit AECs senescence by suppressing the AKT/mTOR/NF-κB signaling pathway. Additionally, EF24 improved mitochondrial dysfunction through induction of mitophagy. Furthermore, EF24 administration significantly reduced the senescent phenotype induced by bleomycin in the lung tissues of mice. Notably, EF24 mitigates fibrosis and promotes overall health benefits in both the acute and chronic phases of IPF, suggesting its therapeutic potential in IPF treatment.
These findings collectively highlight EF24 as a new and effective therapeutic agent against IPF by inhibiting senescence in AECs.
特发性肺纤维化（IPF）的治疗仍然具有挑战性，因为它具有无情的进展、严峻的预后和有效治疗方案的稀缺性。新出现的证据强烈支持加速衰老在肺泡上皮细胞（AEC）中驱动 IPF 进展的关键作用。因此，针对衰老的 AEC 成为 IPF 的一种有前途的治疗策略。
姜黄素类似物 EF24 是姜黄素的衍生物，具有更高的生物活性，包括抗炎、抗肿瘤和抗衰老特性。本研究的目的是阐明 EF24 在治疗 IPF 中的治疗潜力和潜在的分子机制。
使用博来霉素诱导 A549 和 ATII 细胞衰老。使用不同的方法检测衰老标志物，包括衰老相关β-半乳糖苷酶（SA-β-gal）染色、western blot 和 q-PCR。通过微计算机断层扫描（CT）、Masson 三色染色和透射电子显微镜（TEM）验证小鼠气管内给予博来霉素诱导肺纤维化。通过评估 PTEN、AKT/mTOR/NF-κB 信号通路和 mitophagy 的表达，用 western blot 或流式细胞术在体外和体内确定 EF24 在 IPF 中的作用和潜在机制。
我们发现，在 12 种针对 IPF 的化合物中，姜黄素类似物 EF24 是最有前途的候选药物。EF24 治疗可显著降低博来霉素诱导的衰老 AEC 中的衰老生物标志物，包括 SA-β-Gal、PAI-1、P21 和衰老相关 secretory 表型（SASP）。EF24 还能有效抑制由衰老 AEC 或 TGF-β诱导的成纤维细胞激活。我们揭示了 PTEN 的激活是 EF24 通过抑制 AKT/mTOR/NF-κB 信号通路抑制 AEC 衰老的关键。此外，EF24 通过诱导 mitophagy 改善线粒体功能障碍。此外，EF24 给药可显著减少博来霉素在小鼠肺组织中诱导的衰老表型。值得注意的是，EF24 在 IPF 的急性和慢性阶段均可减轻纤维化并改善整体健康状况，表明其在 IPF 治疗中的治疗潜力。
这些发现共同强调 EF24 通过抑制 AEC 衰老成为治疗 IPF 的一种新的有效治疗剂。
