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Dual control of liver regeneration by Nr1d1 homeostasis and Klf2 checkpoint
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  • Published: 13 April 2026

Dual control of liver regeneration by Nr1d1 homeostasis and Klf2 checkpoint

  • Bingyu Ye  ORCID: orcid.org/0000-0001-6772-50631,2 na1,
  • Dejian Xie1 na1,
  • Wenlong Shen  ORCID: orcid.org/0000-0002-2293-55901 na1,
  • Meijuan Yue2,
  • Qinpeng Jin1,2,
  • Xinjie Guo1,
  • Yan Zhang  ORCID: orcid.org/0000-0003-4006-663X1,
  • Ping Li  ORCID: orcid.org/0000-0003-1872-15461 &
  • …
  • Zhihu Zhao  ORCID: orcid.org/0000-0001-7081-89141 

Cell Death Discovery , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Chromatin
  • Nuclear organization

Abstract

Following extensive liver resections, diminished liver regeneration impairs the maintenance or restoration of sufficient functional liver mass. Currently, effective therapies to restore liver regeneration are lacking, rendering liver transplantation the sole treatment option for end-stage liver disease. Therefore, it is imperative to elucidate the regulatory mechanisms underlying liver regeneration. In this study, we employed a multi-omics approach integrating Hi-C, RNA-seq, and ATAC-seq to dissect the early regulatory mechanisms of liver regeneration in rats and mice. Our results indicate that immune and inflammatory processes are markedly enriched during the early phase of regeneration, accompanied by upregulation of glucocorticoids (GCs) and their receptor (GR). First, the expression dynamics of the GC-related circadian gene Nr1d1 and its regulatory network—including Nfκbiα, Arntl, Clock, and Rora—align with chromatin reorganization, leading us to propose that the GC–GR–Nr1d1 axis is involved in maintaining liver homeostasis. Second, the GR-regulated FoxO family is significantly enriched, and the FoxO-associated gene Klf2 exhibits coordinated changes in expression, chromatin accessibility, and chromatin structure. Functional experiments demonstrate that Klf2 negatively regulates hepatocyte proliferation. Hence, we propose the GC–GR–FoxOs–Klf2 axis acts as a checkpoint in hepatocyte proliferation, preventing premature activation of proliferation- and cell cycle-related genes and ensuring orderly and efficient liver regeneration. Our findings on the role of GCs in liver regeneration may further support their future therapeutic application in liver diseases such as liver fibrosis, alcoholic cirrhosis, and hepatocellular carcinoma (HCC).

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Data availability

Rat all sequencing raw data (Hi-C, RNA-seq and ATAC-seq) generated in this study have been submitted to NCBI with a BioProject accession number of PRJNA1104701 (http://www.ncbi.nlm.nih.gov/bioproject/1104701). Mouse Hi-C raw data have been submitted to NCBI with a BioProject accession number of PRJNA1417570 (http://www.ncbi.nlm.nih.gov/bioproject/1417570). Mouse RNA-seq raw data have been submitted to NCBI with a BioProject accession number of PRJNA1417571 (http://www.ncbi.nlm.nih.gov/bioproject/1417571).

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Funding

This work was supported by the National Science and Technology Major Project (2018ZX10305410) to ZHZ, Henan Natural Science Foundation (242300421330) to BYY and the Key Scientific Research Projects of Henan Higher Education (24A180014) to B.Y.Y.

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Author notes

  1. These authors contributed equally: Bingyu Ye, Dejian Xie, Wenlong Shen

Authors and Affiliations

  1. Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China

    Bingyu Ye, Dejian Xie, Wenlong Shen, Qinpeng Jin, Xinjie Guo, Yan Zhang, Ping Li & Zhihu Zhao

  2. State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, China

    Bingyu Ye, Meijuan Yue & Qinpeng Jin

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Contributions

ZHZ conceived and designed the project. BYY, MJY, XJG, QPJ, PL, and YZ carried out the experiments; DJX and WLS carried out the data analysis and interpreted all bioinformatic data. BYY and ZHZ contributed to results interpretation and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yan Zhang, Ping Li or Zhihu Zhao.

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The authors declare no competing interests.

Ethics approval

All animal experiments were conducted in accordance with procedures approved by the ethics committee at Henan Normal University, Henan, China, and conformed to the relevant regulatory standards. All animal studies were completed in the experimental animal center of Henan Normal University, China (license number: HNSD-2025-07-07, licensed by the Ministry of Science and Technology of China).

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Ye, B., Xie, D., Shen, W. et al. Dual control of liver regeneration by Nr1d1 homeostasis and Klf2 checkpoint. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03039-5

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  • Received: 04 December 2025

  • Revised: 23 February 2026

  • Accepted: 06 March 2026

  • Published: 13 April 2026

  • DOI: https://doi.org/10.1038/s41420-026-03039-5

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