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

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 analyzed, 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 signaling, 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 promising strategy in CRC therapy. Induction of alternative cell death pathways may improve response, minimize relapse, and enable combinatorial regimens for resistant tumors.