The microbial metabolite I3A inhibits ferroptosis and the effectiveness of redox-based cancer therapy.

Ferroptosis, a lipid peroxidation-driven form of regulated cell death, has emerged as a promising target for cancer therapy. However, the endogenous metabolic checkpoints restraining ferroptosis remain poorly defined. Here, we identify the tryptophan-derived indole metabolite, indole-3-aldehyde (I3A), as a potent suppressor of ferroptosis. Mechanistically, I3A activates the aryl hydrocarbon receptor to suppress c-Jun N-terminal kinase-c-JUN signaling under oxidative stress. This inhibition of c-JUN limits autophagic flux by downregulating LC3B expression, thereby stabilizing nuclear glutathione peroxidase 4. As a result, I3A not only prevents ferroptosis-associated lipid peroxidation but also mitigates oxidative DNA damage. In mouse models of melanoma and colorectal cancer, I3A administration significantly reduced the antitumor efficacy of the ferroptosis inducer RSL3, accompanied by reduced lipid peroxidation and preserved glutathione peroxidase 4 levels. Furthermore, gut colonization with Lactobacillus reuteri increased I3A concentration and conferred ferroptosis resistance in vivo. Together, these findings identify a host-microbe metabolic axis in which microbial I3A suppresses cancer cell ferroptosis through aryl hydrocarbon receptor-c-Jun N-terminal kinase signaling, which may have critical implications for redox-based cancer therapies.