Salviadione Attenuates Acute Lung Injury by Targeting VDAC1-Mediated Mitochondrial Ferroptosis
Wentao Su1,#, Aishan Gulijiakela1,#, Jihao Xiong1, San Zhang1, Ke Ma2,*
1 Department of Emergency, Huashan Hospital, Fudan University, Shanghai, China
2 Department of Intensive Care Unit, Huashan Hospital, Fudan University, Shanghai, China
* Corresponding Author: Ke Ma. Email: 
# These authors contributed equally to this work
(This article belongs to the Special Issue: Bioactive Natural Components as Regulators of Cellular Pathways and Disease Progression)
BIOCELL https://doi.org/10.32604/biocell.2026.081235
Received 26 February 2026; Accepted 15 May 2026; Published online 08 June 2026
Abstract
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, Fe
2+ 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 Fe
2+ 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.
Keywords
Salviadione; acute lung injury; ferroptosis; BEAS-2B cells; mitochondrial dysfunction; voltage-dependent anion channel 1 (VDAC1); glutathione peroxidase 4 (GPX4)
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