Fuentes-Baile, MaríaGarcía-Morales, PilarPérez-Valenciano, ElizabethMata-Balaguer, TrinidadMenéndez-Gutiérrez, María Pde Juan Romero, CaminoRodríguez-Lescure, ÁlvaroMartín-Orozco, ElenaMallavia, RicardoBarberá, Víctor MSaceda, Miguel2026-04-202026-04-202025-10Biomed Pharmacother. 2025 Oct:191:118541.https://hdl.handle.net/20.500.12105/27436Histone deacetylase inhibitors (HDACis) induce cell death in many chemoresistant cancer models, suggesting their potential as alternative treatments for these malignancies. However, their efficacy in solid tumors remains limited. Therefore, understanding the molecular mechanisms underlying HDACi-induced cell death is essential for developing targeted activators of these pathways, enabling the selective elimination of chemoresistant cancer cells while minimizing the widespread transcriptional effects of HDACis. In this study, we investigated HDACi-induced cell death across models of different cellular origins to determine whether a universal molecular mechanism triggers this process. Our findings demonstrate that HDACi-induced cell death is TP53-independent, resistant to caspase inhibitors, and sensitive to serine protease inhibitors. This form of cell death requires intracellular calcium mobilization to induce mitochondrial depolarization. Using DNA arrays, apoptosis protein arrays, and ELISA assays, combined with siRNA-mediated gene silencing, we identified genes with a causal relationship to TSA-induced cell death. These include dual-specificity phosphatases such as DUSP3 and DUSP10; endoplasmic reticulum stress-related genes such as XBP1, MBTPS1, MBTPS2, and RPS6KA5; and other genes like BAX, AIF, EAF2, NANOS1, and CCNYL1. Our findings reveal novel potential targets for developing antineoplastic agents designed to exploit HDACi-induced cell death pathways, providing a strategy to overcome chemoresistance in cancer therapy.This study has been funded by Instituto de Salud Carlos III and cofunded by the European Union (FEDER) through the projects PI08/0901, PI12/02025 and PI22/00824 M.S and M.S and C.d.J.R (PI22/00824), Consellería de Innovacion, ´ Universidades, Ciencia y Sociedad Digital from Generalitat Valenciana (CIAICO/2022/081) given to M.S. This study was also funded by FISABIO intramural grant through the projects UGP-20–135 granted to M.S.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Caspase-independent cell deathCell-death mechanismsDifferential gene expression analysisEndoplasmic reticulum stressHistone deacetylase inhibitorSerine protease inhibitorAttribution-NonCommercial-NoDerivatives 4.0 International40945274Biomedicine & Pharmacotherapyopen access