AbstractLiver regeneration is an intricate pathophysiological process that has been a subject of great interest to the scientific community for many years. The capacity of liver regeneration is very critical for patients with liver diseases. Therefore, exploring the mechanisms of liver regeneration and finding good ways to improve it are very meaningful.

摘要肝再生是一个复杂的病理生理过程，多年来一直是科学界非常感兴趣的主题。。因此，探索肝再生的机制并找到改善肝再生的好方法是非常有意义的。

Mesencephalic astrocyte-derived neurotrophic factor (MANF), a member of newly identified neurotrophic factors (NTFs) family, extensively expresses in the liver and has demonstrated cytoprotective effects during ER stress and inflammation. However, the role of MANF in liver regeneration remains unclear.

中脑星形胶质细胞源性神经营养因子（MANF）是新发现的神经营养因子（NTFs）家族的成员，在肝脏中广泛表达，并在内质网应激和炎症过程中表现出细胞保护作用。然而，MANF在肝再生中的作用仍不清楚。

Here, we used hepatocyte-specific MANF knockout (MANFHep−/−) mice to investigate the role of MANF in liver regeneration after 2/3 partial hepatectomy (PH). Our results showed that MANF expression was up-regulated in a time-dependent manner, and the peak level of mRNA and protein appeared at 24 h and 36 h after 2/3 PH, respectively.

在这里，我们使用肝细胞特异性MANF敲除（MANFHep-/-）小鼠来研究MANF在2/3部分肝切除术（PH）后肝再生中的作用。我们的结果显示，MANF表达以时间依赖性方式上调，mRNA和蛋白质的峰值水平分别出现在2/3 PH后24小时和36小时。

Notably, MANF knockout delayed hepatocyte proliferation, and the peak proliferation period was delayed by 24 h. Mechanistically, our in vitro results showed that MANF physically interacts with LRP5 and β-catenin, two essential components of Wnt/β-catenin pathway. Specifically, as a cofactor, MANF binds to the extracellular segment of LRP5 to activate Wnt/β-catenin signaling.

值得注意的是，MANF敲除延迟了肝细胞增殖，峰值增殖期延迟了24小时。从机制上讲，我们的体外结果表明，MANF与LRP5和β-连环蛋白（Wnt/β-连环蛋白途径的两个重要成分）发生物理相互作用。具体而言，作为辅因子，MANF与LRP5的细胞外片段结合以激活Wnt/β-连环蛋白信号传导。

On the other hand, MANF interacts with β-catenin to stabilize cytosolic β-catenin level and promote its nuclear translocation, which further enhance the Wnt/β-catenin signaling. We also found that MANF knockout does not affect the c-Met/β-catenin complex after 2/3 PH. In summary, our study confirms that MANF may serve as a novel hepatocyte factor that is closely linked to the activation of the Wnt/β-catenin pathway via intr.

另一方面，MANF与β-连环蛋白相互作用以稳定胞质β-连环蛋白水平并促进其核易位，从而进一步增强Wnt/β-连环蛋白信号传导。我们还发现，在2/3 PH后，MANF基因敲除不会影响c-Met/β-连环蛋白复合物。总之，我们的研究证实，MANF可能是一种新的肝细胞因子，与通过intr激活Wnt/β-连环蛋白途径密切相关。

IntroductionThe liver’s unique ability to repair and regenerate has been widely recognized [1,2,3]. Mature hepatocytes are typically quiescent and highly differentiated, rarely dividing under normal conditions. DNA labeling studies have shown that the percentage of hepatocytes in DNA synthesis in the normal liver is very low, less than 0.2%.

引言肝脏独特的修复和再生能力已被广泛认可[1,2,3]。成熟的肝细胞通常静止且高度分化，在正常条件下很少分裂。DNA标记研究表明，正常肝脏中DNA合成中肝细胞的百分比非常低，不到0.2%。

However, liver regeneration following acute injury is highly beneficial and has been extensively studied. The liver consists of various types of cells, hepatocytes accounting for approximately 80% of liver weight and about 70% of all liver cells [4]. As the primary functional cells of the liver, hepatocytes can proliferate under specific conditions, including surgical removal, chemical injury, and infection [1, 5, 6].

。肝脏由各种类型的细胞组成，肝细胞约占肝脏重量的80%，约占所有肝细胞的70%[4]。作为肝脏的主要功能细胞，肝细胞可以在特定条件下增殖，包括手术切除，化学损伤和感染[1，5，6]。

These cells can rapidly enter the cell cycle to restore liver mass and function.As the liver’s ability to regenerate is crucial for repair and prognosis after partial hepatectomy and liver transplantation, there is an urgent need to gain a better understanding of the molecular and cellular mechanisms of liver regeneration following hepatectomy.

这些细胞可以迅速进入细胞周期以恢复肝脏质量和功能。由于肝脏的再生能力对于部分肝切除术和肝移植术后的修复和预后至关重要，因此迫切需要更好地了解肝切除术后肝再生的分子和细胞机制。

2/3 partial hepatectomy (PH) is a widely used and extensively studied model for liver regeneration in rodents [7]. After 2/3 PH, residual hepatocytes can quickly enter the cell cycle and undergo division to compensate for the lost liver tissues, restoring the original quality and size within a week in rodents [8, 9].

2/3部分肝切除术（PH）是一种广泛使用和广泛研究的啮齿动物肝再生模型（7）。在2/3 PH后，残留的肝细胞可以迅速进入细胞周期并进行分裂以补偿丢失的肝组织，在啮齿动物中在一周内恢复原始质量和大小[8，9]。

Clinically, liver regeneration carries important implications due to the treatment strategies for many liver diseases, such as liver fibrosis, liver tumor resection, and liver transplantation, all of which depend on the physiological and functional regeneration of the liver. Therefore, elucidating the potential mechanisms and physiological characteristics of liver r.

临床上，由于许多肝脏疾病的治疗策略，例如肝纤维化，肝肿瘤切除和肝移植，肝再生具有重要意义，所有这些都取决于肝脏的生理和功能再生。因此，阐明肝脏r的潜在机制和生理特征。

Data availability

数据可用性

The data analyzed during this study are included in this article and the supplemental data files. The data supporting the findings of this study are available from the corresponding author upon reasonable request.

。根据合理的要求，通讯作者可以提供支持本研究结果的数据。

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Download referencesAcknowledgementsWe thank Prof. Jia Luo for supplying MANF conditional knockout mice.FundingThis work was supported by the National Natural Science Foundation of China (No. U21A20345 to YXS) and the University Natural Excellent Research and Innovation Team Fund of China (No.

下载参考文献致谢我们感谢贾洛教授提供MANF条件性敲除小鼠。基金这项工作得到了国家自然科学基金（YXS编号U21A20345）和中国大学自然优秀研究与创新团队基金（No。

2022AH010046 to YXS).Author informationAuthor notesThese authors contributed equally: Yanyan Liang, Qiong Mei.Authors and AffiliationsSchool of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, ChinaYanyan Liang, Qiong Mei, Enguang He, Chuansheng Wei, Yue Wang, Yue Dong, Jie Zhou, Xiaofang Tao, Wenyan Qu, Mingxia Zhao, Goma Chhetri, Juntang Shao, Yujun Shen, Jun Liu, Lijie Feng & Yuxian ShenBiopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, ChinaYanyan Liang, Qiong Mei, Enguang He, Chuansheng Wei, Yue Wang, Yue Dong, Jie Zhou, Xiaofang Tao, Wenyan Qu, Mingxia Zhao, Goma Chhetri, Limeng Wei, Juntang Shao, Yujun Shen, Jun Liu, Lijie Feng & Yuxian ShenDepartment of Biochemistry, Faculty of Pharmacy, Ege University, Izmir, 35100, TurkeyPetek BallarDepartment of General Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei, 230022, ChinaYuxian ShenAuthorsYanyan LiangView author publicationsYou can also search for this author in.

2022AH010046至YXS）。作者信息作者注意到这些作者做出了同样的贡献：梁艳艳，琼梅。作者及所属单位安徽医科大学基础医学院，合肥，230032，中国梁燕燕，琼梅，何恩光，魏传生，王越，岳东，周洁，陶晓芳，瞿文燕，赵明霞，戈玛·切特里，邵俊堂，沈玉君，刘军，冯丽杰，安徽医科大学神生物制药研究所，合肥，230032，中国梁燕燕，王琼，何恩光，魏传生，王越，董越，周洁，陶晓芳，瞿文燕，赵明霞，戈玛·切特里，魏利梦，邵俊堂，沈玉军，刘军，冯丽杰，沈玉贤艾格大学药学院生物化学系，伊兹密尔，35100，安徽医科大学第一附属医院土耳其皮特·巴拉德普外科，合肥，230022，中国深圳玉县作者Yanyan LiangView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsYYL contributed to the experimental design, data analysis and manuscript writing. QM contributed to the mice sample collection. EGH, CSW, YW, YD, JZ, XFT, WYQ, MXZ, LMW and GC performed the mice and cell experiments. JTS, YJS, JL and LJF provided some research ideas.

PubMed Google ScholarContributionsYYL为实验设计，数据分析和手稿撰写做出了贡献。QM为小鼠样本采集做出了贡献。EGH，CSW，YW，YD，JZ，XFT，WYQ，MXZ，LMW和GC进行了小鼠和细胞实验。JTS、YJS、JL和LJF提供了一些研究思路。

PB revised the manuscript draft and edited the language. YXS designed the whole study, supervised the experiments, and revised the manuscript. All authors approved the manuscript.Corresponding authorCorrespondence to.

PB修改了稿件草稿并编辑了语言。YXS设计了整个研究，监督了实验，并修改了手稿。所有作者都批准了手稿。对应作者对应。

Yuxian Shen.Ethics declarations

沈玉贤。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethics approval

All the animal experiments were reviewed and approved by the Animal Ethics Committee of Anhui Medical University with the approval number LLSC20200022. We ensure that all research was conducted in accordance with ethical principles.

所有动物实验均经安徽医科大学动物伦理委员会审查批准，批准号为LLSC20200022。我们确保所有研究均按照道德原则进行。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by Yufang ShiSupplementary informationSupplementary information: Fig S1 to S7 for multiple supplementary figuresoriginal data from immunoblottingRights and permissions.

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Reprints and permissionsAbout this articleCite this articleLiang, Y., Mei, Q., He, E. et al. MANF serves as a novel hepatocyte factor to promote liver regeneration after 2/3 partial hepatectomy via doubly targeting Wnt/β-catenin signaling.

转载和许可本文引用本文Liang，Y.，Mei，Q.，He，E。等人。MANF作为一种新型肝细胞因子，通过双重靶向Wnt/β-连环蛋白信号传导促进2/3部分肝切除术后的肝再生。

Cell Death Dis 15, 681 (2024). https://doi.org/10.1038/s41419-024-07069-8Download citationReceived: 23 April 2024Revised: 31 August 2024Accepted: 12 September 2024Published: 18 September 2024DOI: https://doi.org/10.1038/s41419-024-07069-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

细胞死亡Dis 15681（2024）。https://doi.org/10.1038/s41419-024-07069-8Download引文收到日期：2024年4月23日修订日期：2024年8月31日接受日期：2024年9月12日发布日期：2024年9月18日OI：https://doi.org/10.1038/s41419-024-07069-8Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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