Effects of Oxaliplatin on Hematopoietic Pathways with Implications for Chronic Pain

Background: Oxaliplatin, a widely used chemotherapeutic agent, is associated with hematologic toxicities such as anemia, leukopenia, and thrombocytopenia. Despite their clinical relevance, the molecular mechanisms underlying lineage-specific bone marrow suppression remain poorly understood. Methods: We administered oxaliplatin to mice over eight weeks and performed bulk RNA-sequencing on bone marrow alongside peripheral blood analysis and cytokine profiling. Transcriptomic data were analyzed to identify differentially expressed genes (DEGs) and enriched pathways, with a focus on hematopoietic and immune lineages. Results: Oxaliplatin induced broad transcriptional suppression of erythropoiesis and lymphopoiesis, with 3,690 DEGs identified (FDR<0.05, |FC|>1.5). Upregulation of Cdkn1a and downregulation of E2f2 suggest G1/S cell cycle arrest, correlating with repression of key erythroid maturation genes (e.g., Spta1, Slc4a1, Alas2) and hemoglobin subunits (Hba-a12, Hbb-bs/t). Despite a ~3000-fold increase in renal Epo expression, bone marrow Epor was reduced, indicating erythropoietin resistance. B and T cell markers were also significantly downregulated, signifying a collapse in adaptive immunity. Notably, neutrophils were largely spared. Cytokine analysis revealed a pro-inflammatory shift with elevated TNF-α and CCL2 and reduced TGF-β, potentially exacerbating hematopoietic dysfunction. The data also point to a neuro-immune axis in which oxaliplatin-induced inflammation in the bone marrow contributes to peripheral nerve sensitization as seen with upregulation of nociceptive signaling components such as Tacr1. Conclusions: Oxaliplatin induces a lineage-dependent suppression of hematopoiesis, driven by coordinated cell cycle arrest, metabolic stress, and disrupted cytokine signaling. These findings provide mechanistic insights into oxaliplatin’s hematologic toxicity linking bone marrow failure and neuropathic pain via interconnected inflammatory and metabolic pathways and may inform therapeutic strategies to mitigate myelosuppression and peripheral neuropathy in cancer patients.