TGF-β1 Promotes the Recovery of Dorsal Root Ganglion Neurons from Cisplatin-Induced Injury Through Smad4-Dependent...

Chemotherapy-induced peripheral (CIPN) neuropathy is a common dose-limiting side effect affecting roughly 30-40% patients. Dorsal root ganglia (DRG) neurons are one of the main targets of CIPN as chemotherapy drugs may accumulate in DRG neurons. Chemotherapy drugs may induce direct damages on DRG neurons while also activating immune pathways, which results in the releasing of pro-inflammatory cytokines. This cascade may also damage neurons and amplify pain signaling. Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with prominent immunomodulatory roles. Here, we report that TGF-β1 can promote axonal regeneration on DRG neurons injured by cisplatin via a suppressor of mothers against decapentaplegic (Smad) signaling pathway. To confirm the involvement of canonical TGF-β signaling, we applied the selective TGF-β type I receptor antagonist SB-431542 and performed a gene knockdown of Smad3 and Smad4, assessing their impacts on TGF-β1's effects. Our results demonstrate that TGF-β1 could significantly enhance axonal regeneration in DRG, largely through a Smad4-dependent pathway, and we propose TGF-β1/Smad4 as a promising molecular target for treating CIPN.