裸鼹鼠 (NMR) Heterocephalus glaber 被称为最长寿的啮齿动物，对缺氧和癌症具有极强的抵抗力。此处，NMR 胚胎成纤维细胞 (NEF) 及其小鼠对应物 (MEF) 均处于缺氧条件（0% O2、5% CO2）下。然后采用比较转录组学和蛋白质组学的组合来识别差异表达基因（DEG）。值得注意的是，我们观察到 NEF 和 MEF 之间组蛋白 H1.2（由 HIST1H1C 编码）积累水平不同。随后的机制分析表明，NEF 中 H1.2 的较高表达与其抑制剂 PARP1 的较低表达相关。此外，我们发现H1.2可以直接与HIF-1α PAS结构域相互作用，从而通过促进与HIF-1β的二聚化来促进HIF-1α的表达。还发现 H1.2 的过度表达可通过 NRF2/P62 信号通路触发自噬并抑制癌细胞的迁移以及异种移植肿瘤的形成。此外，工程化的 H1.2 敲入小鼠模型在缺氧条件（4% O2）下表现出显着延长的存活率，并降低了肿瘤形成率。总的来说，我们的结果表明 H1.2 与缺氧适应和癌症抗性的双重现象之间存在潜在的机制联系。版权所有：© 2024 Du 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

The naked mole rat (NMR), Heterocephalus glaber, is known as the longest-lived rodent and is extraordinarily resistant to hypoxia and cancer. Here, both NMR embryonic fibroblasts (NEFs) and their mouse counterparts (MEFs) were subjected to anoxic conditions (0% O2, 5% CO2). A combination of comparative transcriptomics and proteomics was then employed to identify differentially expressed genes (DEGs). Notably, we observed distinct levels of histone H1.2 (encoded by HIST1H1C) accumulation between NEFs and MEFs. Subsequent mechanistic analyses showed that higher H1.2 expression in NEFs was associated with the lower expression of its inhibitor, PARP1. Additionally, we discovered that H1.2 can directly interact with HIF-1α PAS domains, thereby promoting the expression of HIF-1α through facilitating the dimerization with HIF-1β. The overexpression of H1.2 was also found to trigger autophagy and to suppress the migration of cancer cells, as well as the formation of xenograft tumors, via the NRF2/P62 signaling pathway. Moreover, an engineered H1.2 knock-in mouse model exhibited significantly extended survival in hypoxic conditions (4% O2) and showed a reduced rate of tumor formation. Collectively, our results indicate a potential mechanistic link between H1.2 and the dual phenomena of anoxic adaptation and cancer resistance.Copyright: © 2024 Du et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.