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Background Pelvic chemoradiotherapy (CRT) is a cornerstone in the treatment of digestive and reproductive system malignancies, such as colorectal and cervical cancers. However, CRT-induced hematopoietic dysfunction severely compromises patient survival and therapeutic outcomes. Hematopoietic stem cells (HSCs), the essential pillars for maintaining blood system homeostasis, are highly sensitive to CRT-induced DNA damage and bone marrow microenvironment disruption. Current clinical interventions, including growth factors and blood transfusions, are primarily reactive and provide only short-term relief, failing to fundamentally mitigate hematological toxicity. Emerging evidence identifies ferroptosis as a driver of HSC functional exhaustion; however, specific interventions remain scarce.Methods To investigate the role of the gut microbiota in radiochemotherapy-induced bone marrow suppression, we established a murine model and performed metagenomic sequencing of fecal samples to profile microbial communities. This was integrated with untargeted-metabolomics on intestinal contents and transcriptomics on host tissue to identify microbiota-derived metabolites correlating with host transcriptomic changes during bone marrow injury. Integrative bioinformatic analysis pinpointed specific bacterial species and metabolites, including vanillylamine, which were significantly associated with hematopoietic suppression. Computational molecular docking predicted high-probability interactions between vanillylamine and key regulatory proteins. The functional role of vanillylamine was validated through co-culture assays with purified hematopoietic stem cells (HSCs), and mechanistic pathways were dissected using immunofluorescence, western blotting, qPCR, flow cytometry, and fluorescence in situ hybridization. Results Mechanistically, Vanillylamine promotes the nuclear translocation of NRF2 within HSCs, subsequently upregulating the expression of downstream antioxidant genes, including HO-1, GPX4, and SLC7A11. This activation effectively suppresses the ferroptotic process, thereby reducing the sensitivity of HSCs to radiation and cytotoxic drugs.Conclusions We achieved enhanced protection of the hematopoietic system against CRT-induced injury. Our findings highlight a microbiota-based strategy for HSC preservation and provide a promising scientific basis for improving the safety and efficacy of pelvic chemoradiotherapy.