ERβ/circAHNAK Axis Inhibits USP10-FMR1 Deubiquitination to Prevent m⁶A-Mediated ADAM17 Decay and Promote Angiogenesis in Clear Cell Renal Cell Carcinoma.

Estrogen receptor β (ERβ), a nuclear hormone receptor, plays multifaceted roles in tumorigenesis, including transcriptional regulation and noncoding RNA signaling. In clear cell renal cell carcinoma (ccRCC), ERβ is frequently overexpressed and associated with enhanced angiogenesis, a hallmark of aggressive tumor progression. However, the mechanisms linking ERβ signaling to the post-transcriptional and post-translational regulation of angiogenic drivers remain poorly defined. In this study, circAHNAK is identified as a direct downstream effector of ERβ and is significantly upregulated in ccRCC tissues. Elevated circAHNAK in ccRCC cells promotes angiogenesis-related phenotypes in HUVECs by stabilizing ADAM17, a metalloprotease known to facilitate tumor angiogenesis. Mechanistically, ERβ enhances circAHNAK expression by transcriptionally activating its host gene. CircAHNAK binds to FMR1, preventing USP10-mediated deubiquitination of FMR1 at Lys593 and thereby accelerating FMR1 proteasomal degradation. In turn, loss of FMR1 impairs the recognition of m⁶A-modified transcripts, thereby blocking METTL14-mediated m⁶A-dependent decay of ADAM17 mRNA. Consequently, ADAM17 accumulates in ccRCC cell-derived exosomes, driving angiogenesis in ccRCC. Overall, these findings define a novel ERβ/circAHNAK/FMR1/ADAM17 axis that integrates USP10-mediated deubiquitination with FMR1-mediated m⁶A modification to promote ADAM17 expression and angiogenesis in ccRCC. Targeting this pathway may represent a promising therapeutic strategy for ccRCC.