Chrono-metabolic regulation of hepatic fibrosis via NR1D1-mediated hepatic stellate cell activation

Table 2 Experimental evidence linking NR1D1 to HIF-1α inhibition and ammonia-mediated hepatic stellate cell activation

Pathway/target	Model/cell type	Intervention	Main findings	Mechanistic insight	Ref.
NR1D1–HIF-1α	LX2, primary HSCs	CCl4-induced fibrosis/NR1D1 overexpression	NR1D1 restoration suppressed HIF-1α, reduced α-SMA and collagen	NR1D1 inhibits HIF-1α signaling, reduces ammonia-mediated HSC activation	[20,29]
Ammonia	LX2, human HSCs	NH4Cl/hyperammonemia	Increased proliferation, ROS, ER stress, α-SMA, PDGF-Rβ	Ammonia promotes HSC activation; toxicity reversed by NR1D1	[12,41]
HIF-1α	HSCs	Hypoxia/metabolic stress	Upregulated fibrogenic genes	HIF-1α drives ammonia-induced fibrogenesis	[19,29]

This table summarizes experimental studies investigating the NR1D1–HIF-1α–ammonia axis, including models, interventions, main findings, mechanistic insights, and supporting references. HSC: Hepatic stellate cell; ROS: Reactive oxygen species; ER: Endoplasmic reticulum; α-SMA: Alpha-smooth muscle actin; PDGF-Rβ: Platelet-derived growth factor receptor beta.