METTL14 mediates the m6A methylation of miR-29a-3p, thereby activating the MAP2K6 signaling pathway and exacerbating the inflammatory response associated with spinal tuberculosis.

Publication date: Jul 08, 2025

Spinal Tuberculosis (STB) constitutes a common form of tuberculosis and is more widespread in developing countries. Not only is it one of the principal causes of spinal deformity but also it may trigger severe neurological impairments, thereby significantly influencing the quality of life of patients. Additionally, microRNAs (miRNAs) participate in the signal transduction among macrophages through multiple means. In the earlier work of our research group, spinal tuberculosis tissues were subjected to miRNA differential analysis and sequencing. The results indicated that miR-29a-3p was under-expressed in patients with spinal tuberculosis relative to the normal population. Nevertheless, it remains unknown at present how methyltransferase 14(METTL14)-mediated miR-29a-3p regulates the inflammatory response of spinal tuberculosis via the Mitogen-Activated Protein Kinase Kinase 6(MAP2K6) signaling pathway. This study aimed to validate the expression levels of METTL14 and miR-29a-3p in spinal tuberculosis and explore the regulatory role of METTL14 in mediating miR-29a-3p via the MAP2K6 signaling pathway during spinal tuberculosis-associated inflammation. Twenty cases of peripheral blood samples from patients with spinal tuberculosis and normal individuals were collected respectively. Through the construction of a BCG-infected THP-1 macrophage model, the expression of METTL14 and miR-29a-3p in spinal tuberculosis was verified by means of clinical sample analysis and cell experiments such as RT-qPCR, immunohistochemistry, and Western blot. The regulation of METTL14-mediated miR-29a-3p through the MAP2K6 signaling pathway in the inflammatory response of spinal tuberculosis was explored via immunofluorescence, RT-qPCR, and ELISA. The expressions of METTL14 and miR-29a-3p were significantly downregulated in patients with spinal tuberculosis, while the expression of MAP2K6 was upregulated. METTL14 regulated the expression of miR-29a-3p through m6A modification, thereby targeting and inhibiting the expression of MAP2K6. Overexpression of METTL14 and miR-29a-3p could suppress the MAP2K6 signaling pathway, alleviated inflammatory responses and spinal tissue damage; conversely, inhibition of METTL14 and miR-29a-3p activated the MAP2K6 signaling pathway, intensifying inflammatory responses and spinal tissue damage. This research uncovers the crucial role of the METTL14/ miR-29a-3p/ MAP2K6 axis in spinal tuberculosis, providing experimental evidence for the utilization of non-coding RNA as molecular targets in spinal tuberculosis, providing references for the study of the pathogenesis of spinal tuberculosis, and offering novel ideas and perspectives for the diagnosis and treatment of spinal tuberculosis. This indicates that the treatment targeting METTL14 may provide a new strategy for the treatment of STB and facilitate its early clinical detection.

Original Article