Grape Seed Proanthocyanidins Enhance Time-Dependent HO-1 Activation and Improve Redox Homeostasis in Obesity-Induced Hepatic Dysfunction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by impaired metabolic flexibility, oxidative stress, and disruption of the temporal coordination of hepatic processes. Obesogenic diets contribute to this dysfunction by altering redox homeostasis and autophagy, thereby promoting lipid accumulation and cellular stress. In this study, we investigated whether grape seed proanthocyanidin extract (GSPE), a polyphenol-rich compound with antioxidant properties, can modulate these alterations in a time-dependent manner. Male Fischer 344 rats were fed a standard or cafeteria diet and supplemented with GSPE (25 mg/kg) at the onset of the active phase (ZT12). Liver samples were collected across four Zeitgeber times to evaluate circadian-related proteins, autophagy markers, antioxidant responses, lipid content, and metabolomic profiles. Cafeteria feeding disrupts hepatic homeostasis, reducing BMAL1 protein levels, altering the temporal organization of autophagy markers, and impairing redox regulation. GSPE did not restore core clock protein expression but induced a pronounced, time-specific activation of the NRF2/HO-1 axis, with a marked increase in HO-1 at the onset of the active phase. This effect was associated with a metabolic shift toward amino acid-related pathways linked to redox balance. These findings indicate that GSPE enhances antioxidant defenses in a time-dependent manner, improving redox–metabolic coordination under obesogenic conditions.