Exosomal lncRNA FENDRR Orchestrates Immune Remodelling and Ferroptosis in the Comorbidity of Lung Cancer and Type 1 Myocardial Infarction.

Abstract

Lung cancer and Type 1 myocardial infarction (T1MI) increasingly co-occur, yet the molecular basis underlying their interaction remains unclear. In this study, we combined multiomics profiling, in vivo and in vitro models and human clinical samples to investigate the regulatory role of the exosomal long noncoding RNA FENDRR in cancer-cardiovascular comorbidity. We found that FENDRR was markedly elevated in thrombus-derived exosomes from T1MI patients and promoted cardiomyocyte ferroptosis and ferritinophagy through the NCOA4-GPX4-P62 axis, thereby exacerbating myocardial injury. Silencing FENDRR significantly alleviated cardiac damage in the T1MI rat model. In contrast, FENDRR was consistently downregulated across multiple cancers, particularly lung adenocarcinoma (LUAD). Higher FENDRR expression was associated with favourable patient survival, and time-dependent ROC analysis demonstrated robust prognostic performance in LUAD (5 - year AUC = 0.990). Multiomics and immunogenomic analyses further revealed that FENDRR expression correlated with distinct remodelling of the tumour immune microenvironment, including alterations in immune cell infiltration, immune activation scores, chemokine and HLA gene expression and antigen-presentation capacity. These findings were supported by single-cell analyses and by enhanced CD8T-cell and Treg infiltration in thrombi from patients with LUAD and T1MI. Collectively, our results identify FENDRR as a context-dependent regulator that promotes myocardial injury but may exert tumour-suppressive and immune-modulatory functions in lung cancer. These insights provide a mechanistic framework for cancer-cardiovascular comorbidity and highlight FENDRR as a potential biomarker and therapeutic target across disease contexts.