SIRT3-Dependent Actions of Berberine: From Molecular Therapies to Toxicity.

Berberine, an alkaloid with broad bioactive properties, exerts its pleiotropic effects by modulating SIRT3, a mitochondrial NAD+-dependent deacetylase. This review examines the dual role of SIRT3 as a target of berberine in the management of various disorders while also addressing its associated toxicological profiles. The antihyperglycemic effects of berberine are mediated through SIRT3 inhibition, which promotes hyperacetylation of complex I subunits, degradation of MPC1, an increased AMP/ATP ratio, AMPK activation, and suppression of PEPCK1, collectively resulting in the inhibition of gluconeogenesis. In contrast, the hypolipidemic, cardioprotective, and hepatoprotective effects of berberine are associated with SIRT3 activation, which facilitating adipose tissue remodeling, enhancing β-oxidation in NAFLD, promoting lipophagy in diabetic cardiomyopathy, and mitigates doxorubicin-induced cardiotoxicity. Furthermore, berberine exhibits antitumor duality, exerting contrasting effects in colorectal cancer and hepatoma models, and demonstrates versatile mitochondrial metabolic reprogramming in polycystic ovarian syndrome. Notably, ocular toxicity associated with berberine has been linked to SIRT3 inhibition in photoreceptors cells. Overall, the therapeutic versatility of berberine is fundamentally associated with its context-dependent modulation of SIRT3, positioning it as a promising mitochondrial epigenetics modulator for conditions such as metabolic syndrome, NAFLD, and DCM. However, its therapeutic application must be carefully balanced against organ-specific toxicity risks.