Targeting neuroblastoma with 3β,5α-tetrahydrocorticosterone: Activation of aryl hydrocarbon receptor inhibits tumor growth, metastasis, and stemness while promoting neural differentiation

Neuroblastoma (NB) is a highly malignant pediatric cancer that originates from the sympathoadrenal lineage of the neural crest. Recent studies have suggested the aryl hydrocarbon receptor (AHR) pathway as a promising therapeutic target for NB. In this study, we investigated the therapeutic potential of 3β,5α-Tetrahydrocorticosterone (3β-THB) for NB by activating AHR signaling. By means of homology modeling and docking simulations, we demonstrated that 3β-THB binds strongly to the PAS-B domain of human AHR. Experimental validation further confirmed that 3β-THB promotes the nuclear translocation of AHR and upregulates AHR downstream gene CYP1A1 in NB cells, suggesting the AHR agonist role of 3β-THB. In vitro evaluation of its efficacy demonstrated that 3β-THB significantly inhibited NB cell proliferation, promoted neural differentiation, and induced cell cycle arrest at the G0/G1 phase. Additionally, 3β-THB treatment increased apoptosis, reduced metastatic potential, and suppressed tumorsphere growth in NB cells. The expression of the NB oncogenic driver MYCN and markers associated with stemness was also inhibited by 3β-THB. In vivo, 3β-THB significantly suppressed tumor growth in both xenograft and TH-MYCN transgenic mouse models, with improved survival rates and minimal liver or kidney toxicity. These findings underscore the potential of 3β-THB as a powerful AHR agonist for treating neuroblastoma.