Androgen receptors protect against thoracic aortic dissection via inhibiting ferroptosis of vascular smooth muscle cells in male patients.

[BACKGROUND] The development of thoracic aortic dissection (TAD) is closely associated with the loss of vascular smooth muscle cells (VSMCs). Androgen receptor (AR) signaling has increasingly been recognized as an important regulator of cell death in prostate cancer. However, the role of AR signaling in the development of TAD in men remains unknown.

[METHODS] The expression of AR was analyzed in clinical specimens obtained from TAD patients undergoing surgical aortic replacement and control subjects receiving heart transplantation. Using β-aminopropionitrile (BAPN)-induced aortic dissection mouse models, we systematically investigated the protective role of AR through multiple approaches. Histopathological evaluation was performed using immunohistochemistry and immunofluorescence. Primary vascular smooth muscle cells were isolated for functional studies including AR knockdown, ferroptosis assessment, and metabolic profiling. Mechanistic insights were gained through chromatin immunoprecipitation, luciferase reporter assays, and RNA stability tests. Seahorse extracellular flux analysis and targeted metabolomics were employed to characterize metabolic alterations.

[RESULTS] The expression of AR in VSMCs was downregulated in both clinical samples and animal models of TAD. Using in vitro and in vivo models, we demonstrate a novel function of AR that inhibits ferroptosis in VSMC by promoting excessive lipid peroxidation. Mechanistically, we show that AR counter-regulates the expression levels of acyl-CoA synthetases ACSL3 and ACSL4 in VSMCs. AR acts as a transcriptional regulator to promote the transcription of ACSL3 gene while inhibiting the transcription of the ACSL4 gene, both of which inhibit lipid peroxidation and ferroptosis. Importantly, activating AR signaling is beneficial in preventing TAD from developing and progressing in the animal model.

[CONCLUSIONS] Our results reveal a previously unrecognized role of AR in TAD pathogenesis and uncover the opposite yet complementary regulation of ACSL3/ACSL4 levels involved in lipid peroxidation-driven ferroptosis in VSMCs.