Acrylamide (ACR), a common dietary pro-oxidant generated in heat-processed foods, disrupts mitochondrial redox homeostasis. While its neurotoxic effects are recognized, the role of ACR in depression remains poorly understood. We hypothesized that dietary ACR exposure promotes depression via SIRT3-dependent mitochondrial oxidative injury. Through
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Acrylamide (ACR), a common dietary pro-oxidant generated in heat-processed foods, disrupts mitochondrial redox homeostasis. While its neurotoxic effects are recognized, the role of ACR in depression remains poorly understood. We hypothesized that dietary ACR exposure promotes depression via SIRT3-dependent mitochondrial oxidative injury. Through an integrative approach combining network toxicology (to prioritize candidate targets), transcriptomics, and Mendelian randomization (MR), we identified SIRT3 as the central mediator. Molecular dynamics simulations demonstrated that ACR’s primary metabolite glycidamide (GA) formed more stable and rigid complexes with key targets (including SIRT3, TP53, CASP3, JUN, PTGS2, and PTK2) than ACR itself, as evidenced by superior structural stability, reduced flexibility, and enhanced hydrogen bonding. Transcriptomic analysis of the human prefrontal cortex (datasets GSE54567 and GSE54568) revealed mitochondrial deacetylase sirtuin 3 (
SIRT3) as the most significantly suppressed gene in depression (
p < 0.01), suggesting an impairment in Superoxide dismutase 2 (SOD2)-mediated antioxidant defense. MR further established
JUN and
PTK2 as causal genetic risk factors for depression (
JUN: Odds Ratio (OR) = 1.029, 95% CI = 1.002–1.057;
PTK2: OR = 1.040, 95% CI = 1.005–1.076;
JUN (OR) = 1.048, 95% CI = 1.021–1.076,
PTK2: OR = 1.073, 95% CI = 1.039–1.109) of each MR estimates, while other candidates lacked genetic support. Our findings demonstrate that ACR induces depression primarily through SIRT3 suppression, activating JUN/PTK2 pathways, suggesting its potential role in environmental toxicant-induced redox imbalance.
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