β-mangostin triggers ER stress-mediated mitochondrial dysfunction to induce apoptosis in colorectal cancer

BACKGROUND: β-Mangostin (BM), a bioactive xanthone derived from the pericarp of Garcinia mangostana L., exhibits antitumor potential; however, its efficacy and mechanisms in colorectal cancer (CRC) remain unclear. PURPOSE: To evaluate the antitumor activity of BM against CRC and elucidate its underlying mechanisms. METHODS: The anticancer effects on HCT116 and SW480 cells were evaluated using the CCK-8 assay and xenograft tumor model in vivo. Apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and Ca²⁺ dynamics were analyzed via flow cytometry and fluorescence imaging. The molecular mechanisms were investigated using RNA sequencing and Western blotting. RESULTS: phase arrest. Mechanistically, BM triggered pronounced endoplasmic reticulum (ER) stress, leading to intracellular Ca²⁺ dysregulation and mitochondrial Ca²⁺ overload. This resulted in mitochondrial dysfunction, characterized by MMP collapse, ATP depletion, excessive ROS generation, and subsequent DNA damage. Notably, CHOP knockdown and Ca²⁺ chelation significantly attenuated BM-induced apoptosis, confirming the critical involvement of ER stress-mediated Ca²⁺ signaling. In vivo, BM markedly suppressed tumor growth without observable systemic toxicity. Immunohistochemical analysis further demonstrated increased ER stress and apoptosis markers and reduced proliferation in tumor tissues. CONCLUSION: BM exerts potent antitumor effects in CRC by activating an ER stress-mediated mitochondrial dysfunction axis involving Ca²⁺ imbalance and oxidative stress, highlighting its potential as a promising therapeutic candidate.