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Preprint WatchModerateJune 9th, 2026

Spinal Cord Injury Imprints a Glucocorticoid-Driven Failure State in Hematopoietic Stem Cells

Rodgers, K. A.; Garfinkle, E. A.; Kigerl, K. A.; Asghari, E.; Mifflin, K. A.; Hall, J.; Kulkarni, R.; Wang, C.; Goda, C.; Rodrigues Dias, A. C.; Guan, Z.; Karunasiri, M.; Ma, Q.; Miller, K. E.; Dorrance, A.; Popovich, P. G.

Glucocorticoid receptor-dependent repression of DNA repair genes drives a long-lasting hematopoietic stem cell failure state after spinal cord injury, and glucocorticoid receptor blockade restores durable hematopoiesis.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that glucocorticoid receptor signaling drives a repressive, DNA-repair-deficient failure state in hematopoietic stem cells after spinal cord injury, and that glucocorticoid receptor blockade restores hematopoiesis. The indexed Claidex failure for NR3C1 is exicorilant, a glucocorticoid receptor antagonist that did not improve outcomes in metastatic castration-resistant prostate cancer (exicorilant-mcrpc-gr-bypass-fourth-failure, efficacy_failure). The two records do not contradict each other. The preprint shows that glucocorticoid receptor antagonism produces a measurable on-target benefit in a neurotrauma and hematopoietic context, which suggests the prostate cancer result reflects indication-specific biology rather than a non-functional target. A program revisiting NR3C1 antagonism should treat tissue context and the specific glucocorticoid-driven transcriptional program as the variable that determines benefit.

Abstract excerpt

Spinal cord injury (SCI) triggers systemic pathology beyond the nervous system, including bone marrow failure that can worsen infection risk, anemia, and motor recovery. Here we identify a neuroendocrine mechanism that rapidly imprints long-lasting dysfunction in hematopoietic stem cells (HSCs), which sustain lifelong production of immune cells, red blood cells, and platelets. Rather than mounting a canonical stress-hematopoietic response, SCI HSCs enter a broadly repressed state marked by chromatin closure and suppression of programs required for cell-cycle entry, genome maintenance, and redox defense. This maladaptive state leads to persistent DNA damage, impaired oxidative stress resolution, pancytopenia, and loss of long-term HSC regenerative capacity. Mechanistically, SCI-induced glucocorticoid surges drive glucocorticoid receptor-dependent repression of DNA repair genes, including Lig1 and Fen1. Acute glucocorticoid receptor blockade after SCI restores durable hematopoiesis, revealing an early therapeutic window to preserve hematopoietic integrity after neurotrauma.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.