Phytohormone Strigolactams Overcomes Oxaliplatin Resistance in Colorectal Cancer by Blocking the Late-Stage Autophagy to Tip the Metabolic Balance toward Ferroptosis

Primary and acquired oxaliplatin (OXA)-resistance remains a major challenge in colorectal cancer (CRC) therapy. In this work, the type-II strigolactam SL 39 was identified as a promising lead compound against OXA-resistant HCT116^R cells. Co-treatment of SL 39 with OXA restored its sensitivity to HCT116^R cells and inhibited xenograft tumor growth. Mechanistically, SL 39-treatment specifically blocked the autophagosome-lysosome fusion in HCT116^R cells without altering lysosomal pH, leading to induction of mitochondrial dysfunctions and lethal accumulation of reactive oxygen species. Additionally, SL 39 also markedly increased lipid peroxidation and suppressed the SLC7A11/GPX4 axis to trigger ferroptosis in HCT116^R cells. Combining SL 39 with OXA delivered a one-two punch: OXA causes DNA damage and oxidative stress, while SL 39 prevents stress resolution─shifting resistant cells toward ferroptotic death. These findings establish that SL 39 blocks late-stage autophagy to tip the metabolic balance toward ferroptosis in chemoresistant CRC, which offers a novel approach to overcome late-stage treatment failure.