胰导管腺癌（PDAC）被认为是人类最具侵袭性的实体肿瘤之一。尽管它的死亡率高，但由于对潜在生物学机制的不完全理解，有效的靶向治疗策略仍然有限。NAP1L基因家族已被认为与各种人类肿瘤的发展和进展有关。然而，NAP1L5（核小体组装蛋白样5）在PDAC中的具体功能和作用尚未完全阐明。因此，在本研究中，我们旨在调查NAP1L5在PDAC中的作用，并探索NAP1L5与其潜在下游分子PHLPP1（PH结构域富含亮氨酸重复蛋白磷酸酶1）在PDAC中的调控关系。我们的研究发现NAP1L5在PDAC中显著上调。此外，体内外实验表明，NAP1L5的敲除抑制了PDAC细胞的增殖。机制上，发现NAP1L5通过在PHLPP1依赖的方式激活AKT/mTOR信号通路来促进PDAC的进展。具体而言，NAP1L5结合到PHLPP1并促进了PHLPP1的泛素化介导的降解，最终导致PHLPP1表达减少。值得注意的是，由NAP1L5招募的TRIM29发现参与促进PHLPP1的K48链化降解。我们的发现表明，NAP1L5过表达通过抑制PHLPP1表达来促进PDAC细胞的增殖。这些新洞见表明，NAP1L5可能是PDAC的潜在治疗靶点。版权所有 © 2023。由Elsevier Inc.出版。

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the most aggressive solid tumours in humans. Despite its high mortality rate, effective targeted therapeutic strategies remain limited due to incomplete understanding of the underlying biological mechanisms. The NAP1L gene family has been implicated in the development and progression of various human tumours. However, the specific function and role of NAP1L5 (nucleosome assembly protein-like 5) in PDAC have not been fully elucidated. Therefore, in this study, we aimed to investigate the role of NAP1L5 in PDAC and explore the regulatory relationship between NAP1L5 and its potential downstream molecule PHLPP1 (PH domain Leucine-rich repeat Protein Phosphatase 1) in PDAC. Our study revealed that NAP1L5 is notably upregulated in PDAC. Moreover, both in vivo and in vitro experiments demonstrated that knockdown of NAP1L5 suppressed the proliferation of PDAC cells. Mechanistically, NAP1L5 was found to promote PDAC progression by activating the AKT/mTOR signalling pathway in a PHLPP1-dependent manner. Specifically, NAP1L5 binds to PHLPP1 and facilitates the ubiquitination-mediated degradation of PHLPP1, ultimately resulting in reduced PHLPP1 expression. Notably, TRIM29, recruited by NAP1L5, was found to be involved in facilitating K48-linked ubiquitination of PHLPP1. Our findings indicate that NAP1L5 overexpression promotes the proliferation of PDAC cells by inhibiting PHLPP1 expression. These novel insights suggest that NAP1L5 may serve as a potential therapeutic target for PDAC.Copyright © 2023. Published by Elsevier Inc.