河南师范大学Guoying Yu和Lan Wang共同合作，近期取得重要工作进展。他们研究提出，CCT6A通过抑制HIF-1α介导的乳酸生成来减轻肺纤维化。相关研究成果2024年5月17日在线发表于《分子细胞生物学杂志》上。

据介绍，特发性肺纤维化（IPF）是一种致命的进行性纤维化肺部疾病。IPF的发展涉及不同的分子和细胞过程，最近的研究表明，乳酸在促进疾病进展方面发挥着重要作用。然而，乳酸代谢的调节机制及其下游效应仍不清楚。分子伴侣CCT6A在各种生物过程中发挥多种功能。

研究人员前期已经确定CCT6A与IPF患者血清乳酸水平之间的潜在关联。在这一工作中，研究人员发现CCT6A在纤维化肺组织的2型肺泡上皮细胞（AEC2）中高表达，并与疾病严重程度相关。乳酸增加了上皮细胞中脂滴的积累。CCT6A通过阻断AEC2中乳酸的产生来抑制脂质合成，并减轻博来霉素诱导的小鼠肺纤维化。

此外，研究结果显示，CCT6A通过驱动HIF-1α的VHL依赖性泛素化和降解来阻断HIF-1α介导的乳酸产生，并进一步抑制纤维化肺中的脂质积聚。

总之，研究人员提出，CCT6A在肺纤维化的乳酸代谢中具有关键的调节作用，针对这些关键分子的策略可能代表肺纤维化的潜在治疗方法。

附：英文原文

Title: CCT6A alleviates pulmonary fibrosis by inhibiting HIF-1α-mediated lactate production

Author: Yan, Peishuo, Yang, Kun, Xu, Mengwei, Zhu, Miaomiao, Duan, Yudi, Li, Wenwen, Liu, Lulu, Liang, Chenxi, Li, Zhongzheng, Pan, Xin, Wang, Lan, Yu, Guoying

Issue&Volume: 2024-05-17

Abstract: Idiopathic pulmonary fibrosis (IPF) is a lethal progressive fibrotic lung disease. The development of IPF involves different molecular and cellular processes, and recent studies indicate that lactate plays a significant role in promoting the progression of the disease. Nevertheless, the mechanism by which lactate metabolism is regulated and the downstream effects remain unclear. The molecular chaperone CCT6A performs multiple functions in a variety of biological processes. Our research has identified a potential association between CCT6A and serum lactate levels in IPF patients. Herein, we found that CCT6A was highly expressed in type 2 alveolar epithelial cells (AEC2s) of fibrotic lung tissues and correlated with disease severity. Lactate increases the accumulation of lipid droplets in epithelial cells. CCT6A inhibits lipid synthesis by blocking the production of lactate in AEC2s and alleviates bleomycin-induced pulmonary fibrosis in mice. In addition, our results revealed that CCT6A blocks HIF-1α-mediated lactate production by driving the VHL-dependent ubiquitination and degradation of HIF-1α and further inhibits lipid accumulation in fibrotic lungs. In conclusion, we propose that there is a pivotal regulatory role of CCT6A in lactate metabolism in pulmonary fibrosis, and strategies aimed at targeting these key molecules could represent potential therapeutic approaches for pulmonary fibrosis.

DOI: 10.1093/jmcb/mjae021

Source: https://academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjae021/7676185searchresult=1