Berberine as a Mitochondrial Metabolic Reprogrammer in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Adaptive Energetic Stress, Quality Control, and Translational Limitations

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to mitochondrial dysfunction, including altered oxidative phosphorylation, disrupted fatty-acid oxidation, redox imbalance, abnormal mitochondrial dynamics, and impaired quality control. Berberine (BBR), a plant-derived isoquinoline alkaloid used as a nutraceutical, has been described both as a partial inhibitor of respiratory-chain complex I and as an intervention that improves mitochondrial function. This narrative review critically synthesizes evidence from hepatoma cells, primary hepatocytes, animal models, and human studies to reconcile these divergent effects. The preclinical literature supports a proposed, context-dependent model in which BBR imposes an energetic constraint during nutrient overload while activating AMP-activated protein kinase- and sirtuin-linked pathways that remodel substrate handling, respiration, redox balance, mitochondrial architecture, and autophagy. The strongest mechanistic evidence supports complex I-associated respiratory remodeling, SIRT3-mediated deacetylation of long-chain acyl-CoA dehydrogenase, SIRT1-mediated stabilization of carnitine palmitoyltransferase 1A, and SIRT1-dependent autophagy. Evidence for consistent mitochondrial biogenesis, selective mitophagy, mitochondria–endoplasmic reticulum contact-site remodeling, mitochondrial DNA danger signaling, and ferroptosis regulation in MASLD remains limited. Human evidence is mixed: a recent placebo-controlled trial found no significant reduction in liver fat with pure BBR, and no included trial directly measured hepatic mitochondrial function or established a mitochondria-mediated clinical effect. Therefore, BBR is best viewed as a context-dependent modulator of hepatic mitochondrial metabolism rather than a uniform mitochondrial enhancer. Pure BBR should not be conflated with whole barberry fruit, uncharacterized botanical preparations, or berberine ursodeoxycholate (HTD1801). Translation requires characterized formulations, exposure-matched models, and direct mitochondria-focused endpoints.