Homoisoflavanone Delays Colorectal Cancer Progression via DNA Damage‐Induced Mitochondrial Apoptosis and Parthanatos‐Like Cell Death

Colorectal cancer remains a major global health challenge, particularly in advanced stages where current therapies show limited efficacy. Natural products, specifically those derived from herbal medicines, provide a valuable resource for discovering novel anticancer agents. In this study, a bioactive homoisoflavanone was successfully isolated and structurally characterized from Polygonatum kingianum, a widely used medicinal herb. In vitro, homoisoflavanone exhibited potent antiproliferative and pro-apoptotic effects in colorectal cancer cells. Mechanistically, homoisoflavanon induced DNA damage mediated mitochondrial apoptosis and parthanatos-like cell death, accompanied by ATM/ATR-Chk1 pathway and PARP activation, loss of mitochondrial membrane potential, elevated ROS levels, and ATP depletion. In vivo, homoisoflavanone significantly suppressed tumor growth in a colorectal cancer xenograft model without inducing systemic toxicity. Immunohistochemical analysis further confirmed decreased proliferation, increased apoptosis, and parthanatos-like cell death in tumor tissues. Collectively, these findings establish homoisoflavanone as a promising plant-derived therapeutic candidate that targets DNA integrity and mitochondrial homeostasis to inhibit colorectal cancer progression, highlighting the potential of herbal medicine-based compounds in anticancer drug development.