Trichostatin A-primed spinal cord organoids alleviate oxidative stress and improve recovery after spinal cord injury involving the NRF2/HO-1 signaling pathway.

Oxidative stress represents a fundamental pathological driver of the secondary injury cascade following traumatic spinal cord injury (SCI). Although the pan-histone deacetylase inhibitor Trichostatin A (TSA) exhibits neuroprotective properties in various contexts, its capacity to modulate the endogenous NRF2/HO-1 antioxidant defense system within the human spinal cord microenvironment remains to be elucidated. In this study, we utilized human induced pluripotent stem cell-derived spinal cord organoids (hSCOs) as a sophisticated, human-relevant platform to investigate these mechanisms. In vitro analyses revealed that TSA preconditioning significantly bolsters the resilience of hSCOs against oxidative damage, manifesting as enhanced cellular viability, diminished accumulation of reactive oxygen species and malondialdehyde, and elevated superoxide dismutase activity. Mechanistic evaluations suggested that this protection is mediated by NRF2 nuclear translocation and subsequent HO-1 upregulation, an effect completely reversed following the pharmacological inhibition of NRF2. Furthermore, the transplantation of TSA-preconditioned hSCOs, encapsulated within a GelMA hydrogel, into a rat contusion model led to marked structural and functional restoration. Compared to untreated organoid grafts, the TSA-primed hSCOs significantly promoted motor function recovery, diminished lesion cavitation, and enhanced neuronal survival, while simultaneously attenuating glial scarring, neuroinflammation, and axonal degeneration. These findings indicate that pharmacological priming with TSA optimizes the therapeutic efficacy of organoid transplantation in a manner involving NRF2/HO-1 activation, establishing a highly promising combinatorial strategy for clinical neural regeneration.