Multi-pathway therapeutics in colorectal cancer: targeting EMT, CSCs, and non-apoptotic cell death for drug resistance reversal

作者：Jiegang Hu, Zhiwei Tang, Narasimha M. Beeraka, Ruixiang Xu, Junqi Liu, Xiang Zhao, Lianghui Li, Ruofan Wang, Thainala Gayathri, Padmanabha Reddy Y, Dilipkumar Reddy Kandula, P. R. Hemanth Vikram, Bhavana Jayadevappa, Bhupalam Pradeepkumar, Zhongshi He · 发表于：Journal of drug targeting · 年份：2025 · DOI：10.1080/1061186x.2025.2600679 · 被引用次数：3 · 研究领域：Cancer Cells and Metastasis、Ferroptosis and cancer prognosis、Autophagy in Disease and Therapy

Colorectal cancer (CRC) is a leading global malignancy, with therapeutic outcomes hampered by chemoresistance from epithelial-mesenchymal transition (EMT), colorectal cancer stem cells (CR-CSCs) and apoptosis evasion. Evidence highlights the therapeutic value of non-apoptotic cell death pathways such as paraptosis, ferroptosis, cuproptosis and autophagy as strategies to overcome resistance. This review evaluates natural and synthetic scaffolds targeting EMT-driven chemoresistance in CRC by inducing regulated cell death pathways and disrupting stemness-associated survival mechanisms. Studies from the last decade were analysed, focusing on EMT regulation, CR-CSC markers (Sox2, Oct4, Nanog), chemoresistance proteins (P-gp, ERCC1) and cell death-inducing agents. Emphasis was placed on compounds modulating Wnt/β-catenin, TGF-β, JAK2/STAT3/GPX4 and p38α pathways. Natural compounds (neferine, ajoene, baicalein, isoliensinine, curcumin analogs) and synthetic drugs (5-FU, oxaliplatin, irinotecan, norcantharidin, cordycepin) modulate EMT and trigger ferroptosis, cuproptosis, paraptosis and autophagy. Mechanistic pathways include HUWE1-TOMM20 axis, CDH17-LGR5 signalling and mitochondrial reprogramming under acidic stress. Additionally, c-Fos-driven stemness, p38α-mediated survival and JAK2/STAT3-regulated GPX4 inhibition were intervention points. Simultaneous targeting of EMT, CR-CSC maintenance and chemoresistance using multifunctional natural and synthetic agents represents a promisin...