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 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 promising strategy in CRC therapy. Induction of alternative cell death pathways may improve response, minimise relapse and enable combinatorial regimens for resistant tumours. EMT activation and CR-CSC enrichment drive chemoresistance in colorectal cancer.Non-apoptotic death pathways (ferroptosis, cuproptosis, paraptosis, autophagy) offer novel therapeutic windows.Natural agents (e.g. baicalein, ajoene, neferine) and synthetics (e.g. NCTD, 5-FU) may modulate EMT and resistance.Targetable pathways include Wnt/β-catenin, JAK2/STAT3/GPX4, p38α and CDH17-LGR5 signalling axes.Multifunctional scaffolds provide a combinatorial approach for targeting tumour plasticity and therapy evasion. EMT activation and CR-CSC enrichment drive chemoresistance in colorectal cancer. Non-apoptotic death pathways (ferroptosis, cuproptosis, paraptosis, autophagy) offer novel therapeutic windows. Natural agents (e.g. baicalein, ajoene, neferine) and synthetics (e.g. NCTD, 5-FU) may modulate EMT and resistance. Targetable pathways include Wnt/β-catenin, JAK2/STAT3/GPX4, p38α and CDH17-LGR5 signalling axes. Multifunctional scaffolds provide a combinatorial approach for targeting tumour plasticity and therapy evasion. This review offers the first integrative perspective on targeting EMT-driven chemoresistance in colorectal cancer through the coordinated induction of apoptosis, paraptosis, ferroptosis, cuproptosis and autophagy. It uniquely emphasises the therapeutic synergy between natural and synthetic agents and highlights underexplored signalling networks (e.g. HUWE1-TOMM20, CDH17-LGR5) as potential leverage points for next-generation CRC therapeutics.