Association of the NOS1AP rs10494366 Genetic Variant With Drug-Induced QT Prolongation.

Hepatic fibrosis (HF) represents a maladaptive wound-healing response triggered by recurrent hepatocyte injury, leading to excessive extracellular matrix (ECM) deposition and its aberrant distribution (). This process is a universal feature of chronic liver diseases and constitutes the pivotal bridge linking persistent inflammation to cirrhosis and, ultimately, hepatocellular carcinoma (). Given the decisive influence of HF on long-term prognosis, halting or reversing fibrogenesis is a therapeutic priority. Viral, parasitic, chemical, pharmaceutical, alcoholic and autoimmune insults can all incite necroinflammatory cascades that converge on hepatic stellate cell (HSC) activation, the central effector of ECM overproduction and progressive scarring (). Consequently, beyond etiology-specific therapy, pharmacological reversal of fibrosis is now regarded as the cornerstone of chronic liver disease management. Substantial experimental evidence has confirmed that suppression of HSC activation markedly attenuates fibrotic progression (). The circadian clock is an evolutionarily conserved endogenous timing system that coordinates physiology, metabolism and behavior with the 24-h light/dark cycle (). In mammals, the master pacemaker resides in the suprachiasmatic nuclei (SCN) of the hypothalamus. Light input via retinal photoreceptors entrains SCN neuronal oscillators and, in turn, aligns subsidiary clocks in virtually every peripheral tissue to the 24-h solar cycle (). These peripheral oscillators operate autonomously in organs such as the liver, kidney, pancreas, skeletal and cardiac muscle; these peripheral clocks sustain rhythmic gene expression through transcriptional-translational feedback loops (). Core components include the heterodimeric transcription factors clock circadian regulator () and basic helix-loop-helix ARNT-like 1 (), the period circadian protein homolog (PER)1-3 and cryptochrome (CRY)1/2 proteins, and nuclear receptors such as Rev-Erbα. The hepatic clock integrates systemic cues with local metabolic demands (). Its architecture comprises input pathways (), a central oscillator (comprising a core loop and a stabilizing loop), and output arms that gate liver-specific rhythms (). Disruption of this network has increasingly been recognized as a pathogenic driver of hepatitis (), steatosis (), fibrosis (), cirrhosis () and hepatocellular carcinoma (). As a basic helix-loop-helix-PER-ARNT-SIM transcription factor, dimerizes with to drive rhythmic expression of -controlled genes governing metabolism, redox balance and cell proliferation (). Rodent models bearing germline mutations exhibit dampened circadian gene expression, metabolic syndrome, cognitive deficits and multi-organ pathology, including accelerated HF, highlighting the non-redundant role of in hepatic homeostasis (). Similarly, genetic ablation of or perturbs hepatic circadian function, resulting in systemic metabolic disturbances, including fasting hyperglycemia, hyperlipidemia, hepatomegaly, and progressive liver pathology characterized by cholangiocyte hyperplasia, chronic inflammation, hepatocyte apoptosis and collagen deposition (). Ginsenosides (GSS) are a standardized saponin-rich extract predominantly derived from the roots of (), and represent one of the most pharmacologically important bioactive fractions of this medicinal herb. The synergistic actions of these compounds underlie a number of documented physiological effects, including immunomodulation, anti-fatigue activity, neuroprotection, glucose and blood pressure homeostasis, and potent antioxidant capacity. Among these properties, the anti-fibrotic potential of individual GSS has received notable attention; for example, Rg3 () suppresses HSC activation and inflammatory cascades (), whereas Rg1 activates the Nrf2-ARE pathway to counteract oxidative stress-driven ECM accumulation (). Building on this foundation, the present study aimed to systematically evaluate the therapeutic impact of GSS in carbon tetrachloride (CCl)-provoked murine fibrosis and in TGF-β1-challenged LX-2 cells, while assessing the functional involvement of the core circadian transcription factor in the fibrotic program, thereby defining a previously uncharacterized chronotherapeutic axis in fibrosis suppression.