Kuklin, Andrii and Slabber, Coenraad Frederik and Tortola, Luigi and Kwan, Chan Lap and Liebisch, Gerhard and Kondylis, Vangelis and Mair, Florian and Kopf, Manfred and Weber, Achim and Werner, Sabine (2025) An Nrf2-NF-KB Crosstalk Controls Hepatocyte Proliferation in the Normal and Injured Liver. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 19 (7): 101480. ISSN 2352-345X,
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BACKGROUND & AIMS: The liver has remarkable regenerative and detoxification capacities, which require the Nrf2 and NF-KB transcription factors. Although their individual functions in hepatocytes are well characterized, knowledge about their crosstalk in the adult liver is limited. METHODS: We performed AAV8-Cre inducible, hepatocytespecific knockout of Nrf2, the NF-KB subunit p65, or both genes to determine the individual and combined roles of these transcription factors in the intact liver of male adult mice and after acute CCl4 injury. Mice were characterized using histologic and immunohistochemical stainings, serum and liver bile acid analysis, flow cytometry, and RNA sequencing. To distinguish between cell-autonomous and non-cell-autonomous mechanisms, we generated and analyzed knockout and knockdown AML12 liver cells. Clodronate liposome-mediated macrophage depletion was used to determine the role of these immune cells in hepatocyte proliferation after CCl4 injection. RESULTS: Loss of p65 alone or p65 in combination with Nrf2 caused spontaneous liver inflammation and necrosis. Gene expression profiling identified individual and common target genes of both transcription factors, including genes involved in the control of cell proliferation. Consistent with the expression of these genes, hepatocyte proliferation was reduced by Nrf2 deficiency under homeostatic conditions and after CCl4 injury, which was rescued by additional loss of p65. The increased hepatocyte proliferation in the double-knockout mice was non-cell-autonomous and correlated with macrophage accumulation in the liver. Depletion of macrophages in these mice suppressed hepatocyte proliferation after CCl4 treatment. CONCLUSIONS: These results reveal a crosstalk between Nrf2 and p65 in the control of hepatocyte proliferation and point to a key role of macrophages in this effect. (Cell Mol Gastroenterol Hepatol 2025;19:101480; https://doi.org/10.1016/j.jcmgh.2025.101480)
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; NRF2; ACTIVATION; INFLAMMATION; REGENERATION; MACROPHAGES; SUPPRESSION; HOMEOSTASIS; COOPERATE; INTEGRITY; Nrf2; p65; Hepatocyte Proliferation; Liver Regeneration |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Jul 2026 09:18 |
| Last Modified: | 28 Jul 2026 09:18 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67310 |
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