Reveals UCHL3's involvement in triggering ferroptosis in intervertebral disc cells, suggesting a critical regulatory mechanism.
Ferroptosis contributes to intervertebral disc degeneration (IVDD), yet its upstream regulatory mechanisms in nucleus pulposus cells (NPCs) remain unclear. Here, we identify a novel UCHL3-HMGB1-NCOA4 signaling axis that drives NPC ferroptosis. Transcriptomic and clinical analyses reveal that UCHL3 is upregulated in degenerative discs, with its expression correlating positively with both IVDD severity and ferroptosis markers. Mechanistically, UCHL3 deubiquitinates and stabilizes HMGB1 by cleaving Lys48-linked polyubiquitin chains, thereby promoting the accumulation of cytoplasmic HMGB1. This stabilized HMGB1 activates NCOA4-mediated ferritinophagy, initiating ferroptosis. Silencing
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Hu et al. (2026) studied this question.
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