Salviadione Attenuates Acute Lung Injury by Targeting VDAC1-Mediated Mitochondrial Ferroptosis

Objective: Mitochondrial dysfunction and ferroptosis contribute critically to acute lung injury (ALI), yet therapies targeting this pathway remain limited. This study investigates whether Salviadione, a rare alkaloid, protects against lipopolysaccharide (LPS)-induced epithelial damage by modulating the mitochondrial ferroptosis pathway. Methods: Network pharmacology, molecular docking, and molecular dynamics simulations identified potential targets. An in vitro model of lung epithelial injury was established using BEAS-2B cells exposed to LPS. Cell viability, lactate dehydrogenase (LDH) release, lipid peroxidation, Fe2+ accumulation, glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, mitochondrial membrane potential (ΔΨm), mitochondrial reactive oxygen species (ROS), and ATP content were measured. voltage-dependent anion channel 1 (VDAC1) silencing and ferroptosis modulators (RSL3, ferrostatin-1) were used for mechanistic validation. Results: Salviadione (10 μM) increased LPS-reduced cell viability from 48.2 ± 3.1% to 82.5 ± 2.7% (p < 0.05) and decreased LDH release by 41.3% (p < 0.05). It reduced lipid peroxidation (by 58.6%, p < 0.05) and Fe2+ accumulation (by 47.2%, p < 0.05), restored GPX4 expression (to 86.4 ± 4.2% of control), and normalized ACSL4. Mitochondrial ΔΨm improved by 2.1-fold (p < 0.01), mitochondrial ROS decreased by 53.4% (p < 0.05), and ATP content increased by 2.3-fold (p < 0.05) versus LPS alone. VDAC1 knockdown abolished Salviadione’s protective effects, while RSL3 reversed and ferrostatin-1 enhanced its actions. Conclusion: Salviadione protects lung epithelial cells from LPS-induced injury by stabilizing VDAC1, preserving mitochondrial function, and inhibiting ferroptosis via the VDAC1/GPX4 axis. These findings establish a foundation for Salviadione-based therapies targeting mitochondrial ferroptosis in ALI.