miR‑27b‑3p modulates CD4+CD39+ Tregs to drive immune‑mediated intervertebraldisc degeneration.

Intervertebral disc degeneration (IVDD) is a major cause of chronic back pain, yet its molecular mechanisms remain poorly understood despite its high prevalence. In the present study, the significant role of microRNA (miR)‑27b‑3p in regulating 731 immune cell types was systematically uncovered utilizing Mendelian randomization (MR) and single‑cell RNA sequencing, with a particular focus on CD4⁺CD39⁺ regulatory T cells (Tregs); and its critical impact on immune‑mediated IVDD progression was highlighted. A total of 76 miRs were screened and, through MR analysis, a significant causal relationship between miR‑27b‑3p and IVDD was identified. Subsequent in vivo and in vitro experiments demonstrated that miR‑27b‑3p overexpression not only promoted apoptosis of nucleus pulposus cells but also accelerated IVDD by modulating the immune functions of CD4+CD39+ Tregs. Single‑cell RNA sequencing further revealed a marked upregulation of immune‑related genes in degenerated discs, particularly those involved in immune cell migration, inflammation and apoptotic regulation pathways. These findings suggest that miR‑27b‑3p plays a pivotal role in IVDD by influencing various immune cells, especially CD4+CD39+ Tregs, underscoring its potential as a therapeutic target with significant clinical implications. Further research into the mechanisms of miR‑27b‑3p could open new avenues for IVDD treatment strategies, offering promising possibilities for future clinical applications.