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

ABSTRACT 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.