Drug-likeness evaluation and inhibitory mechanism of emodin derivative
on cardiac fibrosis based 2 on metastasis-asspcoated protein
Abstract
Background: Previous research demonstrated that emodin inhibits cardiac
fibrosis through metastasisasspcoated protein 3 (MTA3), but its limited
bioavailability hinders clinical application. Aim: To enhance emodin
clinical potential, a new derivative, emodin succinyl ethyl ester, was
synthesized by modifying the 3’-OH position. This study assessed its
drug-likeness, anti-fibrotic properties, and molecular mechanisms
involving MTA3. Methods: Drug-likeness properties of the emodin
derivative were evaluated using computational-aided drug design (CADD)
approaches. An animal model of transverse aortic constriction
(TAC)-induced cardiac fibrosis and Angiotensin II (AngII) stimulated
cardiac fibroblasts were used in vivo and ex vivo, respectively, to
determine the effects of emodin derivative on cardiac fibrosis and
fibroblast transdifferentiation. Bioinformatics analysis of the PROMO
database, CADD, chromatin immunoprecipitation (ChIP), luciferase
reporter assays, and functional experiments were employed to predict,
identify and validate the relationship between MTA3 and its upstream
transcription factors. Results: Emodin derivative exhibited superior
drug-likeness and anti-fibrotic effects compared to emodin by
effectively inhibiting cardiac fibroblast transdifferentiation and
restored MTA3 expression. E2F1 was identified and validated as a
transcriptional regulator, promoting α-SMA and COL1A2 expression, and
directly reducing MTA3 expression in cardiac fibroblasts. The emodin
derivative demonstrated stronger binding to E2F1 transcription site than
emodin, reducing E2F1 expression and enhancing anti-fibrotic action via
MTA3. Conclusion: The emodin derivative shows improved drug-likeness and
potent inhibition of cardiac fibrosis by targeting E2F1, disrupting its
pro-fibrotic function, restoring MTA3 expression, and halting fibrosis
progression. This advances emodin’s potential as a clinical therapy for
cardiac fibrosis and provides insights into its anti-fibrotic
mechanisms.