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

Table 4 Key controversies in NR1D1–HIF-1α–ammonia axis research

Controversy	Evidence/context	Knowledge gap	Ref.
Disease-specific applicability	Most mechanistic studies performed in CCl4-induced fibrosis or NASH/MASH models; relevance to ALD, drug-induced fibrosis, congenital fibrosis, or NAFLD unclear	Uncertain if NR1D1–HIF-1α–ammonia axis functions similarly across diverse etiologies; need multi-model validation	[12,41,53-55]
Single-target vs integrated chrono-metabolic therapy	NR1D1 modulation alone shows anti-fibrotic effects; bioactive compounds (e.g., dihydroartemisinin, notoginsenoside R1) regulate multiple HSC pathways including lipophagy, PPAR-γ/TGF-β	Whether single-node targeting is sufficient vs combinatorial strategies integrating NR1D1, ammonia-lowering therapy, bile acid modulation, and circadian-aligned dosing	[20,21,29,32,55,56]
Clinical translation challenges	Variability in circadian rhythms, fibrosis stage, etiology-specific metabolic alterations; existing models often do not reflect human heterogeneity	Optimal dosing schedules, patient stratification, and model selection; incorporation of patient-derived systems for translation	[4,16,21,30,57]

This table summarizes key issues, supporting evidence, and gaps in knowledge for the NR1D1–HIF-1α–ammonia axis, highlighting areas requiring further investigation. HSC: Hepatic stellate cell; NASH: Nonalcoholic steatohepatitis; MASH: Metabolic dysfunction-associated steatohepatitis; ALD: Alcoholic liver disease; NAFLD: Nonalcoholic fatty liver disease.