Epigenetic Regulation of Ferroptosis by the KDM3A/BRPF1 Transcriptional Axis Confers Neuroprotection in Postpartum Depression mouse model.

BACKGROUND

Postpartum depression (PPD) represents a debilitating perinatal psychiatric disorder with elusive pathogenesis. While ferroptosis-an iron-dependent regulated cell death pathway-is implicated in neuropsychiatric conditions, its mechanistic role in PPD remains undefined.

METHODS

We integrated blood-derived protein quantitative trait loci (bd-pQTL) from 35,559 Icelanders with FerrDb-curated ferroptosis genes through bidirectional Mendelian randomization (MR) to identify causal PPD regulators. Mediation MR delineated ferroptosis-related pathways validated in an ovariectomy/hormone-withdrawal mouse model simulating postpartum neuroendocrinology. Multimodal assessment combined behavioral phenotyping, ferroptotic biomarker quantification, transcriptional profiling, and pharmacological ferroptosis inhibition (Ferrostatin-1).

RESULTS

Primary MR identified 159 ferroptosis-related genes, with BRPF1 exerting robust protection against PPD (IVW OR = 0.797, P = 0.009). Chromatin modifier KDM3A governed BRPF1 expression (mediation β = 0.336, P < 0.0001), forming a causal hierarchy that suppressed ferroptosis. Hormone-withdrawn mice recapitulated PPD neuropathology: depression-like behaviors (FST/TST immobility ↑, OFT/LDT exploration ↓, P < 0.0001), ferroptotic signatures (hippocampal Fe2+↑, GSH↓, P < 0.001), and KDM3A/BRPF1 axis suppression (GPX4↓, SLC7A11↓, P < 0.001). Ferrostatin-1 administration rescued behavioral deficits, normalized redox homeostasis, and restored KDM3A/BRPF1-mediated GPX4/SLC7A11 transactivation (P < 0.01).

CONCLUSIONS

We establish an epigenetic paradigm wherein KDM3A orchestrates BRPF1-dependent transcriptional control of ferroptosis defenses (GPX4/SLC7A11), constraining PPD pathogenesis. This KDM3A/BRPF1 axis represents a druggable target, with ferroptosis inhibition demonstrating therapeutic efficacy, informing novel epigenetic-based interventions.