β-Carboline Alkaloids from Tetrastigma hemsleyanum and Their Bioactivity Against Cardiomyocytes Injury: An in Silico, in Vitro, and in Vivo Study Focusing on Ferroptosis.

BACKGROUND

Doxorubicin (DOX) is a cornerstone of current cancer treatment. However, its clinical application is significantly limited by doxorubicin-induced cardiomyopathy (DIC), with ferroptosis of cardiomyocytes being a primary factor in the development of DIC. It is therefore imperative that new strategies targeting ferroptosis are developed with a view to alleviating DIC. Tetrastigma hemsleyanum Diels et Gilg is a plant that has been utilized in traditional Chinese medicine for a variety of purposes, including detoxification, antitumour activity, anti-inflammatory effects, and cardiovascular protection.

PURPOSE: Thisstudy aims to investigate the effects of β-carboline alkaloids isolated from T. hemsleyanum on ferroptosis in cardiomyocytes, as well as the potential cardioprotective effects of the preferred compound and its role in DIC.

METHODS

Four β-carboline alkaloids isolated from T. hemsleyanum were screened for their ability to inhibit ferroptotic cell death in cardiomyocytes. Comprehensive studies have elucidated the role of desbromoarborescidine A (DesA, compound 2) in mitigating doxorubicin-induced cardiac damage and ferroptosis in mouse hearts, as well as its regulatory mechanisms. The cardiac protective effects of DesA on DIC mice were assessed by measuring cardiac function indicators, cardiac tissue damage, inflammation, and fibrosis levels. Subsequent analyses were conducted using Western blotting, immunohistochemistry, immunoprecipitation, and molecular docking in order to detect ALOX15 degradation, the expression levels of the ALOX15-PEBP1 complex, and key indicators associated with ferroptosis.

RESULTS

A novel β-carboline alkaloid desbromoarborescidine E (DesE, compound 1) along with three known tetrahydro-β-carboline alkaloids, all showed the anti-ferroptotic activity, which were isolated from the aerial parts of T. hemsleyanum. It is noteworthy that DesA treatment markedly alleviated doxorubicin-induced cardiac dysfunction, ferroptosis and fibrosis in mice. From a mechanistic perspective, DesA can bind to ALOX15 and promote its ubiquitination and degradation, thereby inhibiting the formation of the ALOX15/PEBP1 complex, and in turn this limits doxorubicin-induced lipid peroxidation and ferroptosis.

CONCLUSION

These findings demonstrate that DesA protects against DOX-induced cardiomyocyte lipid peroxidation and ferroptosis in cardiac injury by targeting the ALOX15 pathway. Consequently, DesA is a promising lead compound for the development of novel therapeutic agents to treat clinical doxorubicin-induced cardiomyopathy.