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

Psychological stress activates the sympathetic–adrenal axis, elevating norepinephrine (NE) and suppressing reproductive hormones, thereby impairing male reproduction. Excess NE overactivates and desensitizes β‐adrenergic receptors (β‐ARs), triggering Sertoli cell ferroptosis and disrupting spermatogenesis. This study identifies a novel NE–β‐ARs–ferroptosis axis linking stress to testicular injury, and shows that blocking β‐ARs signaling or ferroptosis mitigates the damage. Abstract 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. Psychological stress activates the sympathetic–adrenal axis, elevating norepinephrine (NE) and suppressing reproductive hormones, thereby impairing male reproduction. Excess NE overactivates and desensitizes β-adrenergic receptors (β-ARs), triggering Sertoli cell ferroptosis and disrupting spermatogenesis. This study identifies a novel NE–β-ARs–ferroptosis axis linking stress to testicular injury, and shows that blocking β-ARs signaling or ferroptosis mitigates the damage. Abstract 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 β 1 - and β 2 -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. Advanced Science, Volume 12, Issue 48, December 29, 2025.