circFAM53B-1 and circFAM53B-2 drive VSMC phenotypic modulation via ISG15-mediated suppression of SRF

Although circRNAs have been widely studied in various disease contexts, their roles in vascular smooth muscle cells (VSMCs) phenotypic modulation remain incompletely understood. This study aims to investigate the regulatory functions and molecular mechanisms of two newly identified circRNAs, circFAM53B-1 and circFAM53B-2, in VSMCs phenotypic switching. Here, we show that both circFAM53B-1 and circFAM53B-2 were upregulated by PDGF-BB in a KLF4-dependent manner. They decreased VSMCs contractile markers α-SMA and SM22α levels by suppressing the expression of serum response factor (SRF). Mechanistically, the PDGF-BB-KLF4-circFAM53B1/2 axis enhanced ISG15 expression, which in turn promoted SRF degradation via the ubiquitin-proteasome pathway, subsequently facilitating VSMCs phenotype switching. This study identifies circFAM53B-1 and circFAM53B-2 as key regulators of VSMCs phenotypic switching via the ISG15-SRF pathway. These findings provide new insights into the molecular mechanisms underlying vascular remodeling and suggest potential therapeutic targets for related diseases. Further research is needed to clarify the precise regulation of ISG15 by circFAM53B-1/2 and to evaluate their in vivo therapeutic potential.