Resetting the fibrotic liver clock: NR1D1 couples Hedyotis diffusa to the HIF-1/urea-cycle-ammonia axis and stellate cell activation

Table 1 Circadian clock components and regulators implicated in liver fibrosis

Circadian component/regulator	Model/context	Main fibrosis-related finding	Key pathways/mechanistic features	Ref.
PER1	Schistosoma japonicum-infected mouse model; primary mouse HSCs; JS-1 and LX-2 cells	PER1 restrains hepatic stellate cell activation in schistosomiasis-associated liver fibrosis. PER1 silencing increases fibrogenic gene expression and largely abolishes the antifibrotic effect in HSCs	PER1 functions as an antifibrotic clock gene in HSCs and mediates suppression of HSC activation, with reduced COL1A1, α-SMA, and TIMP1 expression; its expression is directly induced by glucocorticoid receptor signaling	Tang et al[9], 2025
NR1D1	CCl4-induced mouse liver fibrosis model; TGF-β1-treated LX-2 cells	NR1D1 is downregulated in fibrotic liver and activated HSCs. Its activation attenuates collagen deposition, HSC activation, and fibrogenic gene expression, whereas its inhibition exacerbates fibrosis	NR1D1 acts as an upstream negative regulator of the NLRP3 inflammasome; suppresses NLRP3, ASC, caspase-1, and downstream IL-1β/IL-18 signaling; reduces α-SMA, COL-1, and TGF-β1 expression, thereby limiting HSC activation and inflammatory fibrogenesis	Wang et al[10], 2025
NR1D1	CCl4-induced mouse liver fibrosis model; rhythm-disrupted mouse models; primary mouse HSCs and LX-2 cells	NR1D1 disruption disturbs the circadian clock in HSCs, promotes persistent HSC activation, and increases susceptibility to aggravated fibrosis in mice, whereas NR1D1 overexpression alleviates fibrosis	NR1D1 deficiency reduces DRP1 S616 phosphorylation, weakens mitochondrial fission, increases mitochondrial fusion and mtDNA release, activates cGAS inflammatory signaling, and enhances the profibrotic inflammatory microenvironment	Chen et al[11], 2023
CLOCK (ClockΔ19 mutant)	CCl4-induced mouse liver fibrosis model; primary HSCs	Circadian disruption caused by CLOCKΔ19 reprograms qHSCs into a primed profibrotic state. This transcriptional and chromatin-level shift predisposes HSCs to accelerated activation and worsened fibrosis after injury	The CLOCK regulome is linked to maintenance of HSC quiescence; hepatic fibrosis/HSC activation, ECM organization, and RhoGDI signaling are upregulated, whereas FXR/RXR, PXR/RXR, PPARα-related metabolic programs, fatty acid oxidation, and retinoid metabolism are downregulated	Jokl et al[3], 2023
BMAL1	CCl4-induced mouse liver fibrosis model; primary mouse HSCs; TGF-β1-treated LX-2 cells	BMAL1 is downregulated in fibrotic liver and activated HSCs. BMAL1 overexpression suppresses glycolysis, inhibits HSC proliferation and phenotypic transformation, and attenuates liver fibrosis	BMAL1 inhibits HSC glycolytic reprogramming through the IDH1/α-KG axis, reducing HK2 and PKM2 expression, lactate production, and ECAR, thereby decreasing α-SMA and COL1A1 expression and ECM deposition	Xu et al[12], 2022
PER2	CCl4-induced mouse liver fibrosis model; fibrosis regression model; HSC-T6 cells	Loss of PER2 aggravates CCl4-induced liver fibrosis, increases HSC activation, and impairs fibrosis resolution. PER2 overexpression promotes HSC apoptosis and suppresses HSC proliferation	PER2 promotes activated HSC apoptosis via CHOP-dependent upregulation of TRAIL-R2/DR5; mPer2 deficiency is associated with increased TGF-β1, TNF-α, COL1A1, TIMP1, and TIMP2, enhanced α-SMA expression, and reduced fibrosis regression	Chen et al[13], 2010

HSC: Hepatic stellate cell; α-SMA: α-smooth muscle actin.