Norepinephrine Induces Sertoli Cell Ferroptosis via Receptors Desensitization Causing Stress-Related Male Reproductive Dysfunction

Psychological stress poses a significant threat to male reproduction; however, the underlying molecular mechanisms remain poorly understood. Stress-induced hyperactivation of the sympathetic nervous system triggers the secretion of norepinephrine (NE), a key mediator implicated in various pathophysiological processes. Although NE is linked to male reproductive dysfunction, the precise mechanism remains unclear. Here, it is demonstrated that psychological stress can induce Sertoli cell ferroptosis through NE, which is characterized by iron overload, lipid peroxidation, and altered expression of ferroptosis-related proteins. Blockade of β-adrenergic receptors (β-ARs) with propranolol alleviated stress-induced damage, inhibiting ferroptosis and promoting spermatogenesis. In vitro, selective β₁- and β₂-AR antagonists reversed NE-induced Sertoli cell ferroptosis. Mechanistically, NE activated β-arrestin1, driving β-ARs desensitization and internalization, which subsequently stimulated inhibitory G proteins (Gi), suppressed CREB1-dependent GPX4 transcription, and promoted ferroptosis. The findings reveal NE-induced β-ARs desensitization as a mechanistic driver of Sertoli cell ferroptosis. β-ARs signaling modulation is proposed as a potential therapeutic approach for alleviating stress-associated male reproductive impairment.