Hu Yumeng, Hu Yifu, Zhang Shaobo, Guo Yuanyuan, Wang Fangxia, Du Yongxing, Wang Lijuan, Li Pengxue, Xu Yan, Zhang Hui, Yang Zhikai, Liu Zhihua, Xu Jingyong, Liu Mingyang
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100370, China.
Cancer Lett. 2025 Apr 1;614:217523. doi: 10.1016/j.canlet.2025.217523. Epub 2025 Feb 6.
Pancreatic cancer (PC) cachexia, characterized by profound muscle wasting and systemic inflammation, remains a formidable clinical challenge due to its multifactorial nature and complex molecular underpinnings. This study delves into the intricate interplay between microRNA (miRNA) dysregulation and ferroptosis, a form of iron-dependent cell death, in PC cachexia. Specifically, we identified tumor-derived miR-203a-3p as a pivotal miRNA that promotes muscle atrophy by upregulating muscle ferroptosis. Our findings revealed that miR-203a-3p targets zinc finger E-box binding homeobox 1 (ZEB1), subsequently enhancing the expression of the iron transporter solute carrier family 11 member 2 (SLC11A2), thereby facilitating ferroptosis-associated skeletal muscle cell death. Through in vivo experiments using a PC cachexic mouse model, we demonstrated that inhibiting ferroptosis effectively attenuated muscle wasting, highlighting its critical role in the pathogenesis of PC cachexia. These results provide a molecular framework elucidating how miRNA regulation and ferroptosis converge to drive muscle atrophy, offering novel therapeutic avenues for mitigating cachexia in PC patients. By targeting these pathways, we aim to improve muscle preservation and overall survival in this devastating disease.
胰腺癌恶病质以严重的肌肉萎缩和全身炎症为特征，由于其多因素性质和复杂的分子基础，仍然是一个严峻的临床挑战。本研究深入探讨了微小RNA（miRNA）失调与铁死亡（一种铁依赖性细胞死亡形式）在胰腺癌恶病质中的复杂相互作用。具体而言，我们确定肿瘤来源的miR-203a-3p是一种关键的miRNA，它通过上调肌肉铁死亡来促进肌肉萎缩。我们的研究结果表明，miR-203a-3p靶向锌指E盒结合同源框1（ZEB1），随后增强铁转运蛋白溶质载体家族11成员2（SLC11A2）的表达，从而促进与铁死亡相关的骨骼肌细胞死亡。通过使用胰腺癌恶病质小鼠模型进行的体内实验，我们证明抑制铁死亡可有效减轻肌肉萎缩，突出了其在胰腺癌恶病质发病机制中的关键作用。这些结果提供了一个分子框架，阐明了miRNA调控和铁死亡如何共同导致肌肉萎缩，为减轻胰腺癌患者的恶病质提供了新的治疗途径。通过靶向这些途径，我们旨在改善这种毁灭性疾病中的肌肉保存和总体生存率。
