Fucoidan Alleviates Chemotherapy-Induced Peripheral Neuropathy via Activating the Gas6/MerTK Signaling Pathway to Reduce Neuroinflammation

Chemotherapy-induced peripheral neuropathy (CIPN), a prevalent dose-limiting toxicity in cancer chemotherapy, remains mechanistically elusive and therapeutically challenging. Neutrophil extracellular trap (NETs)-mediated neuroinflammation constitutes a critical mechanism for CIPN. Oxaliplatin was used to establish a murine CIPN model. Fucoidan could dose-dependently ameliorate mechanical allodynia in CIPN mice while reducing NETs accumulation and neuroinflammation. RNA-Seq profiling identified the anti-inflammatory factor SOCS3 as a pivotal target of fucoidan. SOCS3 knockdown abolished fucoidan's anti-inflammatory efficacy. RNA-seq analysis revealed MerTK, upstream of SOCS3, was significantly downregulated in peripheral nerve tissues of CIPN patients. Fucoidan activated the Gas6/MerTK axis in macrophages. The therapeutic effects were abrogated by the MerTK-specific inhibitor MI, MerTK siRNA, and Gas6 knockout. Furthermore, fucoidan enhanced MerTK-mediated macrophage phagocytosis of NETs and alleviated neuroinflammation. Fucoidan alleviates CIPN through activating the Gas6/MerTK signaling to induce SOCS3-mediated neuroinflammation inhibition and to promote macrophage-mediated phagocytic clearance of NETs. These findings propose a promising drug candidate for CIPN.