Epigenetic H3K4me3 activation of miR-155-5p promotes intervertebral disc degeneration via autophagy and ageing in nucleus pulposus cells

Nucleus pulposus (NP) cell ageing and impaired autophagy - lysosome biogenesis (ALB) are key drivers of intervertebral disc degeneration (IVDD). The upstream epigenetic regulation of transcription factor EB (TFEB), a major ALB regulator, remains elusive. Our study identifies a H3K4me3-associated miRNA pathway that modulates TFEB activity and IVDD progression. Using in vivo and in vitro models, we found that methyltransferase MLL3 knockdown reduces H3K4me3 methylation at the miR-155-5p promoter, suppressing miR-155-5p transcription. MiR-155-5p directly targets FBXO22, indirectly repressing TFEB transcription and exacerbating NP cells ageing and IVDD. Notably, experiments confirmed MLL3 binds specifically to the miR-155-5p promoter, with no interaction detected at the TFEB or FBXO22 promoters. Our data establish a linear H3K4me3/miR-155-5p/FBXO22/TFEB axis in IVDD pathogenesis. We reveal a novel epigenetic crosstalk where H3K4me3 methylation mediates miRNA-driven TFEB regulation, independent of canonical mTOR signaling. These findings enhance understanding of epigenetic mechanisms in autophagy and ageing control and highlight MLL3 and miR-155-5p as potential IVDD therapeutic targets.