Saatçi, ÖzgeAlam, RashedulHuynh-Dam, Kim-TuyenIşık, AynurÜner, MeralBelder, NevinErsan, Pelin GülizarTokat, Ünal MetinUlukan, BürgeÇetin, MetinÇalışır, KübraGedik, Mustafa EmreBal, HilalŞener Şahin, ÖzlemRiazalhosseini, YasserThieffry, DenisGautheret, DanielOgretmen, BesimAksoy, SercanÜner, AyşegülAkyol, AytekinŞahin, Özgür2025-02-202025-02-202024-06-15https://hdl.handle.net/11693/116498Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca²⁺ channel. This causes cytosolic Ca²⁺ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe²⁺ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death, which are reversed upon chelating Ca²⁺ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca²⁺/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca²⁺ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.EnglishCC BY-ND 4.0 DEED (Attribution-NoDerivatives 4.0 International)https://creativecommons.org/licenses/by/4.0/Cell-deathEstrogen receptorGene expressionApoptosisKinaseStressProliferationChemotherapyFerroptosisArticle10.1038/s41419-024-06814-32041-4889