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

Table 3 Recent preclinical studies of Hedyotis diffusa and other bioactive compounds targeting the NR1D1-HIF1-ammonia axis

Compound/extract	Model	Intervention	Main findings	Mechanistic insight	Ref.
Hedyotis diffusa	CCl4/HF mice, LX2	Hedyotis diffusa extract/injection	Reduced α-SMA, collagen; restored NR1D1	Modulates NR1D1–HIF1–ammonia axis; normalizes urea cycle	[21,29]
Dihydroartemisinin	CCl4 mice, HSCs	Dihydroartemisinin treatment	Restored lipid droplets in HSCs; inhibited activation	NR1D1-mediated Rab7 ubiquitination regulates lipophagy	[32,51,52]
Ferulic acid	LX2 cells, SD rats	TGF-β1/CCl4	Inhibited α-SMA, collagen, p-Smad 2/3	Blocks TGF-β/Smad signaling	[31,47]
Eriocitrin	TAA mice, LX2 cells	Eriocitrin treatment	Reduced inflammasome activation and collagen deposition	PPARα-mediated NLRP1/NLRC4 pathway	[33]
HDW extract	CCl4 mice	HDW treatment	Reduced HSC activation; improved liver function	Modulates gut microbiota, FXR/SHP/CYP7A1 pathway; chrono-metabolic effects	[21]
FA11	CCl4 mice	FA11 treatment	Reduced α-SMA, collagen	Inhibits TGF-β1-induced HSC activation	[46]
Ghrelin	CCl4 mice	Ghrelin treatment	Decreased HSC proliferation, ECM deposition	Modulates HIF-1α and ROS pathways	[45]
Physalin D	HSCs	PD treatment	Reduced HSC activation	Blocks TGF-β/Smad and YAP signaling	[49]

This table summarizes interventions, experimental models, main findings, mechanistic insights, and references for natural and pharmacological compounds affecting the NR1D1–HIF-1α–ammonia pathway. HSC: Hepatic stellate cell; ECM: Extracellular matrix; ROS: Reactive oxygen species; TGF-β: Transforming growth factor-beta.