The circadian clock controls hepatic stellate cell activation via a BMAL1/CK1ε/REV-ERBα/transgelin signaling pathway
Abstract
Liver fibrosis is a progressive and life-threatening condition with no effective targeted treatments. Growing evidence indicates a two-way relationship between circadian rhythm and fibrogenesis, although the specific molecular signaling pathways involved are still not well understood. The molecular clock, which governs circadian rhythms, regulates metabolic and cellular functions, and its pharmacological manipulation has shown potential as a therapy for organ fibrosis. Although the liver’s molecular clock appeared resilient to the progression of chronic liver disease in humans from steatosis to fibrosis, detectable changes in the daily amplitude of clock genes were observed in a cohort of people living with obesity. We found a clock-controlled signaling pathway that drives hepatic stellate cell (HSC) activation, a key initiating event in fibrosis progression. Interfering with this pathway, either by disrupting the core regulator CLOCK:BMAL1 or activating the nuclear receptors REV-ERBs, significantly reduced HSC activation. We also identified transgelin as the downstream effector of clock-regulated HSC contractility, a characteristic of HSC activation. Transgelin is regulated indirectly by a BMAL1-CK1ε signaling pathway and directly by REV-ERBα. Our findings identify a hitherto undescribed mechanism that links the molecular clock to HSC activation and cell contractile function, which is relevant to human fibrotic diseases. This pathway provides several entry points for drugs to target and disrupt primary fibrogenic signaling. By connecting clock biology to the cellular processes that cause fibrosis, our work also offers a mechanistic basis for chronotherapeutic strategies against chronic liver disease.
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BibTeX
@article{johanns2026circadian,
title = {{The circadian clock controls hepatic stellate cell activation via a BMAL1/CK1ε/REV-ERBα/transgelin signaling pathway}},
author = {Manuel Johanns and Alexandre Berthier and Jimmy Vandel and Sandra Courquet and Marie Lapage and Julie Dub-Chevalier and Manjula Vinod and Ninon Very and Francesco Paolo Zummo and Marie Bobows-Gérard and Georgiana Toma and Céline Gheeraert and Didie Vertomm and Gaëtan Herinckx and Violeta Raverdy and François Pattou and Bart Staels and Jérôme Eeckhoute and Philippe Lefebvre},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = jul,
doi = {10.1073/pnas.2611767123},
url = {https://hal.science/hal-05750246v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - The circadian clock controls hepatic stellate cell activation via a BMAL1/CK1ε/REV-ERBα/transgelin signaling pathway
AU - Manuel Johanns
AU - Alexandre Berthier
AU - Jimmy Vandel
AU - Sandra Courquet
AU - Marie Lapage
AU - Julie Dub-Chevalier
AU - Manjula Vinod
AU - Ninon Very
AU - Francesco Paolo Zummo
AU - Marie Bobows-Gérard
AU - Georgiana Toma
AU - Céline Gheeraert
AU - Didie Vertomm
AU - Gaëtan Herinckx
AU - Violeta Raverdy
AU - François Pattou
AU - Bart Staels
AU - Jérôme Eeckhoute
AU - Philippe Lefebvre
PY - 2026
DA - 2026/07/21
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2611767123
UR - https://hal.science/hal-05750246v1
AB - Liver fibrosis is a progressive and life-threatening condition with no effective targeted treatments. Growing evidence indicates a two-way relationship between circadian rhythm and fibrogenesis, although the specific molecular signaling pathways involved are still not well understood. The molecular clock, which governs circadian rhythms, regulates metabolic and cellular functions, and its pharmacological manipulation has shown potential as a therapy for organ fibrosis. Although the liver’s molecular clock appeared resilient to the progression of chronic liver disease in humans from steatosis to fibrosis, detectable changes in the daily amplitude of clock genes were observed in a cohort of people living with obesity. We found a clock-controlled signaling pathway that drives hepatic stellate cell (HSC) activation, a key initiating event in fibrosis progression. Interfering with this pathway, either by disrupting the core regulator CLOCK:BMAL1 or activating the nuclear receptors REV-ERBs, significantly reduced HSC activation. We also identified transgelin as the downstream effector of clock-regulated HSC contractility, a characteristic of HSC activation. Transgelin is regulated indirectly by a BMAL1-CK1ε signaling pathway and directly by REV-ERBα. Our findings identify a hitherto undescribed mechanism that links the molecular clock to HSC activation and cell contractile function, which is relevant to human fibrotic diseases. This pathway provides several entry points for drugs to target and disrupt primary fibrogenic signaling. By connecting clock biology to the cellular processes that cause fibrosis, our work also offers a mechanistic basis for chronotherapeutic strategies against chronic liver disease.
SN - 0027-8424
SN - 1091-6490
ER -