Transcriptomics-informed phenotypic screening of Rhodiola sachalinensis identifies herbacetin as a cardioprotective...

Rhodiola sachalinensis Boriss. (Crassulaceae) is a traditional Chinese medicinal plant whose roots and rhizomes are used to invigorate qi and promote blood circulation and have been documented for the management of qi deficiency and blood stasis, chest pain, and angina. Consistent with these traditional uses, modern pharmacological studies have reported antioxidant, anti-inflammatory, and cardiovascular protective activities of R. sachalinensis. However, owing to its complex chemical composition, the bioactive constituents contributing to its cardioprotective effects remain poorly defined.

This study aimed to identify cardioprotective constituents of Rhodiola sachalinensis oral solution (RS) through an integrated transcriptomics-informed phenotypic screening strategy and to elucidate the potential mechanisms underlying their effects on cardiac remodeling.

The protective effects of RS were evaluated in an isoproterenol (ISO)-induced cardiac remodeling model, followed by cardiac transcriptomic profiling. Transcriptomic signatures were then integrated with complementary phenotypic assays of phenylephrine-induced cardiomyocyte hypertrophy and transforming growth factor-β1-induced cardiac fibroblast activation to screen a library of 101 candidate constituents. The prioritized compound was further evaluated in ISO-induced cardiac remodeling and myocardial infarction (MI) models.

Transcriptomic profiling of RS-treated hearts identified disease-associated signatures that informed the selection of complementary phenotypic assays for cardiomyocyte hypertrophy and fibroblast activation. Screening of 101 candidate constituents prioritized herbacetin (HBT), a flavonoid showing dual activity in both assays. In vivo, HBT attenuated ISO-induced cardiac dysfunction, cardiomyocyte enlargement, and myocardial fibrosis. These effects were associated with improved mitochondrial ultrastructure, preservation of mitochondrial network integrity, and restoration of ISO-suppressed OPA1 expression. In a complementary MI model, HBT improved cardiac function and reduced adverse remodeling. Mass cytometry (CyTOF) and immunofluorescence analyses further showed that HBT treatment was associated with reduced CCR2-positive inflammatory macrophage features and increased MRC1-positive reparative macrophage features during the early post-MI response.

This study establishes a transcriptomics-informed phenotypic screening strategy for identifying bioactive constituents of RS and identifies HBT as a cardioprotective flavonoid constituent. HBT exhibited protective effects across complementary models of cardiac remodeling, with additional evidence of mitochondrial preservation and altered post-infarction macrophage-associated features in the respective experimental settings. These findings expand the cardiovascular pharmacological understanding of R. sachalinensis and provide a framework for discovering bioactive constituents from complex medicinal plants.