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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\u2014including Nf\u03babi\u03b1, Arntl, Clock, and Rora\u2014align with chromatin reorganization, leading us to propose that the GC\u2013GR\u2013Nr1d1 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\u2013GR\u2013FoxOs\u2013Klf2 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).<\/jats:p>","DOI":"10.1038\/s41420-026-03039-5","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T05:05:30Z","timestamp":1776056730000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual control of liver regeneration by Nr1d1 homeostasis and Klf2 checkpoint"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6772-5063","authenticated-orcid":false,"given":"Bingyu","family":"Ye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejian","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2293-5590","authenticated-orcid":false,"given":"Wenlong","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijuan","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinpeng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinjie","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4006-663X","authenticated-orcid":false,"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1872-1546","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7081-8914","authenticated-orcid":false,"given":"Zhihu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"3039_CR1","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/s41586-024-07376-2","volume":"630","author":"KP Matchett","year":"2024","unstructured":"Matchett KP, Wilson-Kanamori JR, Portman JR, Kapourani CA, Fercoq F, May S, et al. 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