Stress-Induced Catecholamines Attenuate Sorafenib Efficacy by Inhibiting Ferroptosis in β2-adrenergic Receptor Positive Renal Cell Carcinoma

Ferroptosis, an iron-dependent form of non-apoptotic cell death, has emerged as a promising target for novel cancer therapy. While sorafenib, a molecular targeted agent for renal cell carcinoma (RCC), has been implicated in ferroptosis induction, conflicting reports persist. Chronic stress, mediated by catecholamines via β2-adrenergic receptors (ADRB2), is known to promote cancer progression, yet its influence on drug resistance and ferroptosis remains elusive. In this study, we first confirmed ADRB2 expression in RCC through immunohistochemistry of surgical specimens. Using the ADRB2-expressing RCC cell line ACHN, we found that stimulation with the β-adrenergic agonist isoproterenol (ISO) conferred resistance to sorafenib both in vitro and in a mouse stress model—an effect abrogated by ADRB2 knockdown. To assess the involvement of ferroptosis in this resistance mechanism, we employed the ferroptosis inhibitor ferrostatin-1 (Fer-1). Similar to ISO, Fer-1 diminished sorafenib sensitivity in ACHN cells. Ferroptosis inducers erastin and RSL3 markedly reduced cell viability; however, ISO attenuated ferroptosis in ACHN cells. Mechanistically, ISO upregulated DUSP1 expression and inhibited the phosphorylation of ERK1/2, p38, and JNK, all of which contribute to ferroptosis suppression. These findings provide compelling evidence that chronic stress-induced ADRB2 activation promotes sorafenib resistance in certain RCC subtypes by mitigating ferroptotic cell death.