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

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.

To evaluate the antitumor activity of BM against CRC and elucidate its underlying mechanisms.

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.

BM significantly inhibited CRC cell proliferation and induced apoptosis in a dose-dependent manner, accompanied by G₁ 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.

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.