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 HCT116R cells. Co-treatment of SL 39 with OXA restored its sensitivity to HCT116R cells and inhibited xenograft tumor growth. Mechanistically, SL 39-treatment specifically blocked the autophagosome-lysosome fusion in HCT116R 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 HCT116R 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.