Jiang Yuyu, Zhang Yunkai, Wang Xiaohui, Xiang Yan, Wang Zeting, Wang Bo, Ding Yingying, Gao Ying, Rui Bing, Bai Jie, Ding Yue, Chen Chang, Zhan Zhenzhen, Liu Xingguang
National Key Laboratory of Immunity & Inflammation, Department of Pathogen Biology, Naval Medical University, Shanghai 200433, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Naval Medical Center, Naval Medical University, Shanghai 200433, China.
Cell Rep. 2025 Mar 25;44(3):115399. doi: 10.1016/j.celrep.2025.115399. Epub 2025 Mar 12.
Alveolar macrophages (AMs) are crucial for lung homeostasis, and their dysfunction causes uncontrolled fibrotic responses and pulmonary disorders. Protein phosphatases control multiple cellular events. However, whether nuclear phosphatases cooperate with histone modifiers to affect pulmonary fibrosis progress remains obscure. Here, we identified pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) as a key protective factor for pulmonary fibrosis. Transcriptomics and epigenomics data confirmed that PHLPP1 selectively targeted Kruppel-like factor 4 (KLF4) for transcriptional inhibition in AMs. Nuclear PHLPP1 directly bound and dephosphorylated histone deacetylase 8 (HDAC8) at serine 39, thereby enhancing its deacetylase enzyme activity and subsequently suppressing KLF4 expression via the decreased histone acetylation and chromatin accessibility. Thus, loss of PHLPP1 amplified KLF4-centric profibrotic transcriptional program in AMs, while intratracheal administration of Klf4-short hairpin RNA (shRNA) adeno-associated virus ameliorated lung fibrosis in PHLPP1-deficient mice. Our study implies that targeting decreased PHLPP1 in AMs might be a promising therapeutic strategy for pulmonary fibrosis.
肺泡巨噬细胞（AMs）对肺稳态至关重要，其功能障碍会导致不受控制的纤维化反应和肺部疾病。蛋白磷酸酶控制多种细胞事件。然而，核磷酸酶是否与组蛋白修饰因子协同作用以影响肺纤维化进展仍不清楚。在此，我们确定了普列克底物蛋白同源结构域和富含亮氨酸重复蛋白磷酸酶1（PHLPP1）是肺纤维化的关键保护因子。转录组学和表观基因组学数据证实，PHLPP1在AMs中选择性靶向Kruppel样因子4（KLF4）进行转录抑制。核PHLPP1直接结合组蛋白去乙酰化酶8（HDAC8）并使其丝氨酸39位点去磷酸化，从而增强其去乙酰化酶活性，随后通过降低组蛋白乙酰化和染色质可及性来抑制KLF4表达。因此，PHLPP1的缺失放大了AMs中以KLF4为中心的促纤维化转录程序，而气管内给予Klf4短发夹RNA（shRNA）腺相关病毒可改善PHLPP1缺陷小鼠的肺纤维化。我们的研究表明，针对AMs中PHLPP1减少的靶向治疗可能是一种有前景的肺纤维化治疗策略。
