A comprehensive review published in Engineering systematically outlines the regulatory capacity of silent information regulator 3 (SIRT3), a mitochondrial deacetylase termed the “head goose molecule”, and its negentropic mechanism for intervening global metabolic disorders including type 2 diabetes, obesity, and steatotic liver disease. Authored by researchers from the Chinese Academy of Medical Sciences & Peking Union Medical College, the paper integrates accumulated preclinical evidence to clarify how SIRT3 activation coordinates multi-pathway metabolic restoration, while sorting out three categories of candidate SIRT3 activators for chronic metabolic disease management.

Metabolic diseases feature systematic disruptions to glucose homeostasis, lipid metabolism, energy balance, and inflammatory signaling, a pathological progression described as entropy increase that denotes escalating cellular disorder. Unlike other sirtuin family members SIRT1–SIRT7, which display dual beneficial and harmful effects across metabolic conditions, SIRT3 consistently exerts protective effects via substrate deacetylation to reverse disordered biological networks, a process defined as negentropy. The review elaborates four core regulatory axes mediated by SIRT3: It ameliorates insulin resistance and reshapes glycolytic and gluconeogenic flux through deacetylating AceCS2, PDHE1a, and IDH2; it boosts fatty acid oxidation via activating LCAD, MTP, and VLCAD while restraining de novo lipogenesis through the LKB1–AMPK cascade; it sustains mitochondrial energy homeostasis by optimizing ATP synthesis, stabilizing antioxidant enzymes SOD2 and PRDX3, and governing mitochondrial fusion, mitophagy, and biogenesis; it suppresses chronic low-grade inflammation by promoting M2 macrophage polarization, inhibiting NLRP3 inflammasome assembly and blunting NF-κB-mediated proinflammatory cytokine transcription.

The paper further evaluates three classes of SIRT3 activators with distinct action modes. Natural products including berberine, metformin, resveratrol, and honokiol modulate SIRT3 by elevating its expression, boosting intracellular NAD⁺ pools or direct allosteric binding, with several candidates entering phase 2 to phase 4 clinical trials for metabolic dysfunction-associated steatohepatitis and prediabetes. Synthetic small molecules such as SKLB-11A, 2-APQC, and ADTL-SA1215 achieve high isoform selectivity by binding unique allosteric pockets separate from the NAD⁺ catalytic domain, delivering stable deacetylase activation in preclinical cardiac and hepatic injury models. NAD⁺ precursors covering nicotinamide mononucleotide, nicotinamide riboside, and nicotinamide indirectly lift SIRT3 activity by replenishing its indispensable cofactor substrate, with clinical data indicating improved muscle insulin sensitivity and hepatic lipid clearance in overweight populations.

The review also acknowledges existing translational barriers, including tissue-specific divergent responses of SIRT3, insufficiently selective activators, and unresolved long-term safety profiles. The research team notes that framing SIRT3 as a central “head goose molecule”, provides a unified theoretical framework for drug repurposing and targeted compound design, and calls for large-scale multicenter clinical trials to validate the clinical value of SIRT3-targeted intervention strategies for chronic metabolic illnesses.

The paper “Activation of Sirtuin 3, a Promising ‘Head Goose Molecule,’ Triggers the Negentropic Mechanism for Treating Metabolic Diseases,” is authored by Hu Li, Tong Wang, Biao Dong, Zonggen Peng, Jiandong Jiang. Full text of the open access paper: https://doi.org/10.1016/j.eng.2025.12.008. For more information about Engineering, visit the website at https://www.sciencedirect.com/journal/engineering.