miR-16-5p Regulates Ferroptosis by Targeting SLC7A11 in Adriamycin-Induced Ferroptosis in Cardiomyocytes

Abstract

Introduction: Adriamycin (ADR) is commonly used in tumor chemotherapy, but its nonreversible cardiotoxicity severely hampers its clinical application. Ferroptosis is an implicated cause of ADR-induced injury. However, the underlying molecular mechanisms remain poorly understood. This study explored whether ferroptosis is a pivotal pathogenic pathway underlying ADR-induced cardiotoxicity and the possible molecular mechanisms involved. Methods: In vivo and in vitro experimental models were used to study the mechanism of ADR-mediated ferroptosis. Ferroptosis levels were examined in mice and human/rat cardiomyocytes. Mechanistically, the expression levels of SLC7A11 and related miRNAs were examined. Bioinformatics prediction and luciferase reporter assays were used to verify the potential interaction between miR-16-5p and SLC7A11. The biological functions and interaction of SLC7A11 and miR-16-5p were investigated in vivo and in vitro. Results: Our study observed that ADR treatment significantly increased ferroptosis levels in vivo and in vitro. Ferroptosis-related pharmacological interventions further confirmed these results. Our data displayed that the SLC7A11 level was significantly decreased in cardiac tissues and cells, while an increased expression level of miR-16-5p was observed. Moreover, upregulation of SLC7A1 and inhibition of miR-16-5p attenuated ADR-induced cardiomyocyte ferroptosis injury. Interactive rescue experiments showed that the protective effects of miR-16-5p inhibition on ADR-induced cardiomyocyte injury were blocked by SLC7A11 knockdown. Discussion: Based on these findings, targeting miR-16-5p could partially reverse the ADR-induced cardiotoxicity by rescuing the SLC7A11 to attenuate ferroptosis. This study presents a pre-clinical basis to identify miR-16-5p/SLC7A11 as a potential treatment target for ADR-induced cardiotoxicity.

LncRNA SNHG1 knockdown inhibits hyperglycemia induced ferroptosis viamiR‐16‐5p/ACSL4 axis to alleviate diabetic nephropathy

“…Owing to a deeper understanding of disease‐relevant miRNAs and mRNAs and advances in in vivo delivery systems, the administration of miRNA/mRNA‐based therapeutics has recently been shown to be feasible and safe in humans with encouraging efficacy results in early‐phase clinical trials 43 . miR‐16‐5p implicates an essential role of ferroptosis in diseases 18 , 44 . And ACSL4 is a critical determinant of ferroptosis sensitivity which functions in inducing ferroptosis, and its deletion presents an unprecedented resistance to ferroptosis 39 .…”

“…Importantly, bioinformatics analysis also showed the physical interaction between SNHG1 and miR‐16‐5p. In addition, it was reported previously that miR‐16‐5p regulated ferroptosis by targeting SLC7A11 in adriamycin‐induced ferroptosis in cardiomyocytes 18 . However, whether SNHG1 regulates diabetic nephropathy via sponging miR‐16‐5p remains unclear.…”

The Regulation of Ferroptosis by Noncoding RNAs

“…MiR-129-3p reduces the expression of SLC7A11 to induce ferroptosis under Se deficiency conditions, leading to liver damage [258]. MiR-16-5p inhibits SLC7A11 to promote ferroptosis in adriamycin-induced cardiomyocyte injury [259]. Exosomal miR-23a-3p derived from cardiac fibroblasts inhibits SLC7A11 expression to promote ferroptosis in atrial fibrillation [260].…”