Circular rna ror. regulates tgf.r1 by decoying mir-140 in alcohol-exposed lungs and fibroblast

Alcohol ingestion exaggerates transforming growth factor-beta 1 (TGFB1) expression and signaling leading to fibroproliferation. Inhibition of TGF beta receptor type 1 (TGFBR1) mitigates the effect of TGFB1 signaling. We showed that alcohol can modulate microRNA (miRNA) expressions. The mechanism by which alcohol modulates microRNA and how it ties to TGFB1 signaling has not been well elucidated. Circular RNA (circRNAs or circ) emerges as a potential therapeutic target based on its stability, tissue specificity, and its ability to modify miRNAs. In this study, we showed that alcohol upregulates TGFBR1 and circRNA form of retinoic acid receptor-related beta;orphan receptor beta (circ-RORB) in lung fibroblasts (LF) and the lung. We identified miR-140 to have binding sites for both TGFBR1 3 prime UTR and circ-RORB; and alcohol attenuated miR-140 expression in LF and the lung. We demonstrated that inhibition of circ-RORB upregulated miR-140 and completely abrogated alcohol-induced miR-140 suppression. We further showed that inhibition of circ-RORB attenuated alcohol-induced TGFBR1, fibronectin (FN1), and a-smooth muscle actin (aSMA) expressions and myofibroblast development as seen by an attenuation of aSMA stress fiber formation in LF. Lastly, Taken together, these findings identify circ-RORB-miR-140-TGFBR1 axis as a novel mechanism by which alcohol induces TGFB1 signaling and promotes FMD. ### Competing Interest Statement The authors have declared no competing interest.