Background <p>Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse reaction to chemotherapy with limited treatment options. Research has indicated that neutrophil extracellular traps (NETs) are critical for the pathogenesis of CIPN. LPS/HMGB1 serve as important inducers of NETs. Here, we aimed to target the inhibition of NET formation (NETosis) to alleviate CIPN.</p> Methods <p>Oxaliplatin (L-OHP) was used to establish a CIPN model. The mice were pretreated with fucoidan to investigate the therapeutic effect. SR-A1^−/− mice were used to examine the role of scavenger receptor A1 (SR-A1) in CIPN. Bone marrow-derived macrophages (BMDMs) isolated from SR-A1^−/− mice and WT mice were used to investigate the mechanism by which macrophage phagocytosis of NETs alleviates CIPN.</p> Results <p>Clinically, we found that the contents of LPS, HMGB1 and NETs in the plasma of CIPN patients were significantly increased and positively correlated with the VAS score. Fucoidan decreased the LPS/HMGB1/NET contents and relieved CIPN in mice. Mechanistically, fucoidan upregulated SR-A1 expression and promoted the phagocytosis of LPS/HMGB1 by BMDMs. Fucoidan also facilitated the engulfment of NETs by BMDMs via the recognition and localization of SR-A1 and HMGB1. The therapeutic effects of fucoidan were abolished by SR-A1 knockout. RNA-seq analysis revealed that fucoidan increased sqstm1 (p62) gene expression. Fucoidan promoted the competitive binding of sqstm1 and Nrf2 to Keap1, increasing Nrf2 nuclear translocation and SR-A1 transcription. Additionally, the sequencing analysis (16&#xa0;S) of microbial diversity revealed that fucoidan increased the gut microbiota diversity and abundance and increased the Bacteroides/Firmicutes ratio.</p> Conclusions <p>Altogether, fucoidan promotes the SR-A1-mediated phagocytosis of LPS/HMGB1/NETs and maintains gut microbial homeostasis, which may provide a potential therapeutic strategy for CIPN.</p> Graphical Abstract <p></p>