Fosb promotes ferroptosis in vascular smooth muscle cells via the NF-κB pathway to exacerbate abdominal aortic aneurysm progression.

BACKGROUND

Abdominal aortic aneurysm (AAA) is a fatal disease characterized by vascular wall inflammation and matrix remodeling. The inflammatory phenotypic transformation of smooth muscle cells (SMCs) holds a pivotal role in AAA pathogenesis. As an inflammatory regulator, whether FBJ osteosarcoma oncogene B (Fosb) participates in AAA progression by driving SMC phenotypic switching remains unclear.

METHODS

Using the scRNA-seq data from AAA patients, we identified Fosb as a key driver of SMC phenotypic switching through cell clustering annotation, differential gene screening, functional enrichment, and pseudo-time trajectory analysis. An in vitro AAA cell model was established using Ang-II-stimulated T/G HA-VSMC cells. Fosb expression was assessed by qRT-PCR and western blot (WB). AAA cell models with Fosb knockdown or overexpression were constructed to investigate the effects of Fosb on T/G HA-VSMC cell proliferation, apoptosis, migration, invasion, contractile marker protein expression, and inflammatory cytokine secretion via WB, CCK8, Transwell, flow cytometry, and ELISA. Furthermore, WB was applied in detecting ferroptosis and NF-κB signaling pathway protein expression. Kits were employed for the determination of MDA, GSH, and Fe2+ levels, and flow cytometry was for ROS levels. Finally, an Ang-II-induced ApoE-/- mouse AAA model was constructed, and histological staining, WB, IHC, and ELISA were carried out to validate that Fosb boosted AAA ferroptosis and inflammation via the NF-κB pathway in vivo.

RESULTS

Fosb+ inflammatory SMCs were significantly increased in AAA and were key drivers of the transition from a contractile to an inflammatory phenotype. Cellular experiments confirmed that Fosb knockdown reversed Ang-II-induced downregulation of SMC contractile markers and repressed cell migration, invasion, apoptosis, and inflammatory cytokine secretion. Mechanistically, through activation of the NF-κB pathway, Fosb triggered ferroptosis, thus boosting AAA ferroptosis and inflammatory responses. Animal experiments demonstrated that in vivo Fosb knockout ameliorated Ang-II-induced AAA progression in mice.

CONCLUSION

Fosb drives SMC ferroptosis and inflammatory phenotypic switching, via NF-κB pathway activation, thereby reinforcing AAA progression. Targeting Fosb or the ferroptosis pathway may provide new therapeutic strategies for AAA treatment.