Garcinone E suppressed nasopharyngeal carcinoma by disrupting the endoplasmic reticulum–mitochondria–lysosome organelle network and modulating the FOXO1 signaling axis

<title>Abstract</title> <p> Given the limited efficacy of current chemotherapies for nasopharyngeal carcinoma, novel therapeutic agents are urgently needed. Our previous study revealed that Garcinone E inhibits nasopharyngeal carcinoma cell cycle progression, xenograft tumor growth, and autophagic flux, yet the underlying molecular mechanism remained unclear. In this study, S18, HK1, and HONE1 cells were treated with Garcinone E to investigate the molecular mechanism by which Garcinone E suppresses nasopharyngeal carcinoma <italic>in vitro</italic> . We found that Garcinone E induced endoplasmic reticulum stress and ER-phagy, leading to calcium leakage, reactive oxygen species bursts, oxidative stress, and lipid peroxidation, while simultaneously activating intracellular antioxidant defense. Garcinone E triggered mitochondrial fragmentation, loss of membrane potential, ATP depletion, and DNA damage, accompanied by mitophagy activation. Furthermore, Garcinone E caused lysosomal membrane permeabilization, cathepsin leakage, loss of acid phosphatase activity, and lysosomal ubiquitination, promoting TFEB nuclear translocation. Garcinone E also upregulated FOXO1 expression and promoted its nuclear translocation, and FOXO1 knockdown significantly reduced cell viability, suggesting a critical role of FOXO1 in Garcinone E-induced cytotoxicity. Collectively, these findings demonstrate that Garcinone E disrupts the ER-mitochondria-lysosome network and upregulates FOXO1, acting as a novel organelle network-disrupting agent with potent anticancer activity against nasopharyngeal carcinoma. </p>