HSP90阻害剤17-DMAGによるMETTL3調節を介した腎線維症治療の治療的可能性

Kidney fibrosis is a major pathological feature of chronic kidney disease (CKD), characterized by excessive deposition of extracellular matrix proteins, leading to progressive loss of kidney function. N6-methyladenosine (m6A) RNA methylation has emerged as a crucial epigenetic modification implicated in various diseases, including kidney fibrosis. METTL3, an m6A "writer," plays a key role in promoting fibrosis by stabilizing profibrotic gene expression. Therefore, targeting METTL3 represents a promising therapeutic strategy for CKD treatment. In this study, we explored the therapeutic potential of 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in regulating METTL3 to mitigate kidney fibrosis.

Through transcriptome-based drug repositioning, we identified 17-DMAG as a potential inhibitor of METTL3. Differentially expressed gene (DEG) analysis was performed to assess the enrichment of 17-DMAG in CKD-related gene expression profiles. The antifibrotic effects of 17-DMAG were evaluated in vitro and in vivo models. Mechanism of 17-DMAG in downregulating METTL3 was also investigated.

17-DMAG significantly reduced METTL3 expression in renal epithelial cells in a dose- and time-dependent manner. In vivo mouse models of kidney fibrosis, 17-DMAG treatment attenuated METTL3 levels, reduced total m6A modification, and effectively mitigated fibrosis, as evidenced by decreased collagen deposition and profibrotic marker expression. Mechanistically, 17-DMAG, a heat shock protein 90 (HSP90) N-terminal inhibitor, induced a heat shock response that sequentially upregulated HSP70 expression. The elevated HSP70 levels inhibited c-Jun N-terminal kinase (JNK) activity, thereby suppressing the c-Jun transcription factor and ultimately leading to the downregulation of METTL3 expression. MeRIP-Seq analysis revealed that 17-DMAG reversed unilateral ischemia-reperfusion injury-induced m6A epitranscriptomic changes in fibrosis-related genes, including Gsk3b, which is involved in fibrotic pathways.

N-terminal HSP90 inhibition, along with subsequent c-Jun suppression, contributed to the mechanism underlying 17-DMAG-induced METTL3 downregulation. Through this regulatory pathway, 17-DMAG effectively suppressed METTL3 expression and attenuated kidney fibrosis in both in vitro and in vivo models.