Schisandrin B Upregulates Sirtuin 3 and Mitigates Lung Epithelial Injury Induced by Nickel Nanoparticles

NiNPs pose a persistent occupational hazard to the lung. However, it remains unclear whether mitochondrial lipid metabolismcentered on mitochondrial deacetylase Sirt3can be mechanistically modulated to mitigate NiNPs-induced epithelial injury. Here, we integrated GBD contextualization, network toxicology, structure-based docking/molecular dynamics, and mechanistic studies in human lung epithelial cells with Sirt3 gain- and loss-of-function. Acute NiNPs exposure reduced viability, increased ROS, dissipated mitochondrial membrane potential, increased Drp1 and decreased MFN1/MFN2, and suppressed Sirt3. Concomitantly, lipid metabolism-related markers suggested increased lipid synthesis and uptake, reduced expression of the β-oxidation-associated enzyme ACOX1, lipid droplet accumulation, and apoptosis. Sirt3 knockdown exacerbated redox collapse and lipid imbalance, whereas Sirt3 overexpression partially improved mitochondrial and lipid metabolism-related readouts, with reduced apoptosis. In silico analyses suggested stable binding of Sch B to Sirt3, and Sch B treatment was associated with increased Sirt3 expression, dampened inflammatory/profibrotic signaling, partially rescued ACOX1, and alleviated apoptosis. Collectively, these results support a Sirt3-associated mitochondrial-redox and lipid marker axis as a key contributing mechanism in epithelial injury under NiNPs suspension exposure conditions, and Sch B treatment is associated with phenotypic improvement accompanied by increased Sirt3 levels.