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: 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.

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.