Paricalcitol-mediated vitamin D receptor activation attenuates neuronal ferroptosis via cAMP-PKA-DRP1 signaling pathway after intracerebral hemorrhage.

The Vitamin D Receptor (VDR) is an emerging therapeutic target for neurological injuries, yet its role in neuronal ferroptosis and mitochondrial dynamics following intracerebral hemorrhage (ICH) remains undefined. This study aimed to determine if VDR activation protects neurons by regulating mitochondrial fission via the Cyclic Adenosine Monophosphate - Protein Kinase A - Dynamin-related Protein 1 (cAMP-PKA-DRP1) signaling pathway. We utilized a mouse ICH model and a hemin-induced injury model in primary neurons to evaluate the neuroprotective efficacy of the selective VDR agonist, Paricalcitol (PAL). Our results first establish that VDR is a key neuronal target, as its expression is robustly upregulated in perihematomal neurons both in vivo and in vitro. Systemic PAL administration in mice conferred significant neuroprotection, reducing acute neuronal death, suppressing ferroptosis, and preventing excessive mitochondrial fission, which translated into lasting improvements in long-term cognitive function and synaptic integrity. Mechanistically, we demonstrate that PAL's anti-ferroptotic action is a direct neuroprotective effect, independent of microglial hematoma clearance. The core signaling cascade involves VDR-dependent activation of the cAMP-PKA pathway, leading to an increase in the inhibitory phosphorylation of DRP1 at Ser637. The necessity of this pathway was confirmed as the protective effects of PAL were abrogated by VDR knockdown or cAMP inhibition. Critically, its sufficiency was demonstrated as direct activation of the pathway with an agonist mimicked PAL's anti-ferroptotic effects. Collectively, these findings reveal that VDR activation by paricalcitol ameliorates neuronal injury after ICH by directly inhibiting ferroptosis through the cAMP-PKA-DRP1-mediated preservation of mitochondrial integrity, highlighting a potent therapeutic strategy.