Honokiol protects against acute pancreatitis by activating SIRT3 to restore mitochondrial oxidative phosphorylation and alleviate hyperacetylation

Objective: Acute pancreatitis (AP) is a potentially life-threatening inflammatory disease with limited therapeutic options. Although honokiol has shown beneficial effects in animal models of AP, the mitochondrial mechanisms underlying these effects remain poorly understood. This study investigated whether honokiol protects against AP by activating the mitochondrial deacetylase Sirtuin 3 (SIRT3) and regulating Oxidative Phosphorylation (OXPHOS) function.

Methods: A mouse model of caerulein-induced AP was established to assess the temporal expression of SIRT3 and the effects of its pharmacological inhibition. The efficacy of honokiol was evaluated in vivo using an AP mouse model and in vitro using 266-6 cells and primary pancreatic acinar cells. Proteomic analysis was performed to identify SIRT3-regulated mitochondrial proteins and pathways. Protein-protein docking and immunoprecipitation were used to validate the interaction and acetylation of the respiratory complex subunits.

Results: SIRT3 expression was markedly reduced in AP, while its inhibition exacerbated disease severity, confirming a protective role. Honokiol treatment restored SIRT3 expression, alleviated inflammation and mitochondrial damage, and partially rescued OXPHOS protein expression. The proteomic profiling identified three candidate OXPHOS subunits-adenosine triphosphate synthase membrane subunit K, cytochrome c1 (CYC1) and ubiquinol-cytochrome c reductase hinge protein-that were restored by honokiol treatment. The protein-protein docking analysis revealed strong binding affinity between SIRT3 and CYC1. The immunoprecipitation assay further confirmed that honokiol reduced the acetylation of CYC1, indicating that this effect is mediated by SIRT3 activity.

Conclusion: Honokiol activates SIRT3 and promotes deacetylation of the respiratory complex Ⅲ subunit CYC1, contributing to OXPHOS restoration and mitochondrial protection in AP. These findings suggest a previously unrecognized SIRT3-CYC1 signaling axis underlying honokiol's mitochondrial protective effects in AP. Please cite this article as: Miao YF, Yao JQ, Peng Y, Bai D, Fan SH, Li HY, Jin W, Lu Y. Honokiol protects against acute pancreatitis by activating SIRT3 to restore mitochondrial Oxidative Phosphorylation and alleviate hyperacetylation. J Integr Med. 2026; Epub ahead of print.

Acute pancreatitis; Cytochrome c1; Honokiol; Oxidative phosphorylation; Sirtuin3.