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

Abstract

Hepatic fibrosis is a pivotal and reversible stage of chronic liver disease, yet approved antifibrotic therapies remain scarce. In World Journal of Gastroenterology, Xia et al reframes fibrosis as disordered circadian-hypoxia-metabolic crosstalk and highlights NR1D1-centered reprogramming of the HIF-1/urea-cycle-ammonia axis as a testable antifibrotic strategy. After identifying six Hedyotis diffusa injection (HDI)-derived constituents detectable in blood and liver, the authors integrate network pharmacology, Gene Expression Omnibus mining, and liver proteomics to nominate circadian rhythm regulation, hypoxia-inducible factor 1 signaling, and urea-cycle/ammonia metabolism as convergent hubs. In a carbon tetrachloride-induced mouse model, HDI reduces collagen deposition and α-smooth muscle actin expression and improves fibrosis-associated serum indices. Zeitgeber-time sampling indicates disrupted clock gene profiles in fibrotic liver and partial restoration after HDI, with prominent NR1D1 recovery. HDI also reduces hepatic HIF-1α abundance, restores carbamoyl phosphate synthetase 1 activity, and lowers hepatic ammonia. AAV9-mediated NR1D1 knockdown blunts these biochemical and histologic improvements, supporting target dependency. In vitro, ammonium chloride activates LX2 stellate cells and induces mitochondrial hyperfusion, consistent with local ammonia stress amplifying fibrogenic activation. Translational priorities include identifying the active HDI constituents and confirming direct NR1D1 engagement, validating efficacy across etiologic fibrosis models, and assessing ammonia/urea-cycle markers for patient selection, monitoring, and phase-aligned dosing.

Keywords: Circadian rhythm; NR1D1; HIF-1 signaling; Urea cycle; Hepatic stellate cell activation; Hedyotis diffusa injection

Core Tip: Hepatic fibrosis is a pivotal and potentially reversible stage of chronic liver disease, yet approved antifibrotic therapies remain scarce. Xia et al propose that Hedyotis diffusa injection mitigates fibrogenesis by engaging the core clock gene NR1D1, with two downstream branches—suppression of HIF-1 signaling and restoration of urea-cycle/ammonia homeostasis—converging on reduced hepatic stellate cell activation and collagen deposition. This work connects circadian regulation with hypoxia responses and nitrogen metabolism, addressing a key mechanistic gap in liver scarring. By highlighting a druggable clock node and clinically accessible metabolic readouts, it may inform clock-guided antifibrotic development and biomarker-based staging and response monitoring.