Gallic acid relieved bortezomib-induced peripheral neurotoxicity by restoring Schwann cell lysosomal activity

Abstract Bortezomib (BTZ) serves as a first-line medication for multiple myeloma (MM) therapy. Unfortunately, despite its prominent efficacy in MM therapy, BTZ-induced peripheral neuropathy (BIPN) presents a significant challenge for patients lacks an established therapeutic solution. Previous research has demonstrated the involvement of lysosomal dysfunction in Schwann cells as a key in the pathological process of BIPN, suggesting that agents enhancing lysosomal activity could hold promise as a treatment for BIPN. Gallic acid (GA) is a natural compound known to preserve lysosomal integrity. However, it remains unidentified whether GA is effective in ameliorating BIPN. The administration of GA in mice demonstrated a significant reversal of BTZ-induced mechanical hypersensitivity, reduction in tail nerve conduction velocity, and demyelination of the sciatic nerve. GA counteracted BTZ-induced lysosomal dysfunction as evidenced by DQ-Red-BSA staining in RSC96 Schwann cells. BTZ-induced lysosomal protein loss and autophagic flux blockage were also hindered by GA. Further analysis revealed that BTZ resulted in the increased phosphorylation of transcription factor EB (TFEB) and reduced nuclear translocation of TFEB in RSC96 cells, and these effects were reversed upon GA treatment. Importantly, GA did not compromise the cytotoxic effects of BTZ on RPMI 8226 cells, indicating little interference with the pharmacological effects of BTZ. In summary, this study provides compelling evidence that GA can ameliorate BIPN in mice. GA activated TFEB signaling, promoted the lysosomal activity, and thus restored autophagy flux in Schwann cells exposed to BTZ. These findings underscore the potential of GA as a promising therapeutic intervention for BIPN.