Aminopeptidase N: the glucocorticoid gateway linking chronic stress to ferroptosis resistance in liver cancer.

Chronic stress triggers a range of physiological responses that could dysregulate the immune system and metabolic processes, thereby increasing susceptibility to various diseases. In this issue of the JCI, Wu et al. identified a metabolic bridge between chronic stress and liver cancer progression. Chronic stress-induced glucocorticoids promoted aminopeptidase N (ANPEP) expression and subsequent reprogramming of amino acid metabolism, leading to increased liver cancer growth and metastasis. ANPEP facilitated stabilization of the cystine-glutamate transporter system Xc- and increased l-cystine influx, thereby enhancing cellular antioxidant capacity to prevent ferroptosis. Silencing ANPEP in combination with sorafenib treatment showed a synergistic inhibitory effect on liver cancer progression. These findings uncover ANPEP as a valuable target for therapeutic interventions to treat patients with liver cancer experiencing chronic stress.