Berberine as a multitarget modulator of metabolic inflammation: molecular mechanisms, circadian regulation, and translational perspectives.

Metabolic inflammation is a chronic, low-grade inflammatory state sustained by metabolic stress, organelle dysfunction, immune activation, and gut-derived signals. Because these processes are closely interconnected, single-target interventions may be insufficient. Berberine, a plant-derived isoquinoline alkaloid, has attracted attention for its broad metabolic and anti-inflammatory effects. In this review, we summarize evidence that berberine regulates several interacting pathways, including cellular energy sensing, glucose and lipid metabolism, mitochondrial quality control, redox and inflammatory signaling, and gut-liver-microbiota communication. We also discuss circadian regulation as a relevant but still underexplored aspect of berberine action, focusing on BMAL1/CLOCK- and REV-ERBα-related metabolic and inflammatory networks. Current clinical evidence suggests modest benefits for glycemic control, insulin resistance, dyslipidemia, and selected features of steatotic liver disease. However, formulation variability, heterogeneous trial designs, and limited long-term outcome data remain important barriers. Overall, berberine may serve as an adjunctive metabolic modulator, but standardized preparations and time-aware clinical studies are needed.