p53-DDIT4-NF-κB Pathway Drives Depression — Curcumin Blocks It

Depression affects hundreds of millions globally, yet its molecular underpinnings remain poorly understood, limiting targeted treatment development. This study from Shandong University addresses a critical gap: how oxidative stress and neuroinflammation converge in the medial prefrontal cortex (mPFC) to produce depressive behavior, and whether curcumin — a natural polyphenol — can interrupt this process through a defined molecular mechanism rather than nonspecific antioxidant effects.

The research team used male C57BL/6J mice subjected to three weeks of chronic corticosterone (CORT) oral administration, a well-validated model of stress-induced depression. A parallel lipopolysaccharide (LPS) model (1 mg/kg i.p. daily for 14 days) was also employed to confirm findings in an inflammation-driven context. Curcumin (50 mg/kg i.p. daily) was administered during weeks two and three of CORT exposure. Five behavioral tests — open field, sucrose preference, forced swim, tail suspension, and elevated plus maze — were used to quantify depression- and anxiety-like phenotypes. Transcriptomic profiling of mPFC tissue combined with network pharmacology analysis was used to identify key signaling hubs.

CORT-treated mice showed significant depression-like behaviors across all five tests, accompanied by elevated oxidative stress markers (including 8-hydroxydeoxyguanosine, a DNA oxidative damage biomarker), increased inflammatory cytokine production, microglial activation (assessed by Iba-1 immunofluorescence), and reduced dendritic spine density in mPFC neurons on Golgi staining. Curcumin treatment significantly reversed all of these changes — improving sucrose preference, reducing immobility in forced swim and tail suspension tests, lowering oxidative damage, suppressing neuroinflammation, and restoring dendritic architecture.

Transcriptomic analysis and network pharmacology converged on the p53-DDIT4-NF-κB axis as the central signaling hub mediating both CORT-induced pathology and curcumin's therapeutic effects. p53 directly transcribes DDIT4, which in turn activates NF-κB-driven inflammatory gene expression. Molecular docking confirmed a direct interaction between curcumin and p53. Pharmacological validation was decisive: the p53 inhibitor pifithrin-α (PFT-α, 5 mg/kg) replicated curcumin's antidepressant, antioxidant, and anti-inflammatory effects, while the p53 activator NSC697923 (2 mg/kg) abolished curcumin's benefits — demonstrating that p53 suppression is both necessary and sufficient for curcumin's mechanism of action in this model.

These findings carry meaningful implications for both basic neuroscience and translational psychiatry. The identification of p53 as an upstream driver of neuroinflammatory depression — not merely a cancer-related tumor suppressor — opens a new conceptual framework. DDIT4 (also known as REDD1) was already known to suppress mTORC1 and cause synaptic loss in depression models; this study places it downstream of p53 and upstream of NF-κB, creating a coherent three-node pathway. Curcumin's ability to target this axis at the p53 level, confirmed by molecular docking and pharmacological rescue experiments, provides mechanistic specificity that prior curcumin-depression studies lacked. Caveats include the exclusive use of male mice, limiting generalizability, and the reliance on animal models that may not fully recapitulate human MDD biology.