Dihydromyricetin restores lysosomal function in Schwann cells to alleviate bortezomib-induced peripheral neuropathy via ERK/TFEB signaling.

Abstract

Bortezomib (BTZ) serves as a first-line drug for multiple myeloma (MM) treatment by reversibly inhibiting of the proteasomes. However, BTZ-induced peripheral neuropathy (BIPN) remains a significant toxicity concern, with its molecular mechanisms not fully elucidated, resulting in limited therapeutic options. Dihydromyricetin (DHM) has been shown to alleviate neuropathic pain, but its potential effect on BIPN has not been investigated. We found that oral administration of DHM (40 mg/kg/day, 200 mg/kg/day) for 2 weeks significantly improved mechanical allodynia, sciatic nerve conduction, and demyelination in a BIPN mouse model (BTZ 1.0 mg/kg, i.v.). BTZ (50 nmol/L) impaired lysosomal function and blocked autophagy flux in both primary cultured rat Schwann cells and RSC96 Schwann cells; these effects were reversed by DHM treatment (3 μmol/L, 10 μmol/L). Mechanistically, DHM facilitated the nuclear translocation of TFEB, a master regulator of lysosomal-related genes, and the protective effects of DHM on Schwann cells were abolished by Tfeb shRNA. Furthermore, BTZ treatment activated ERK signaling, leading to TFEB phosphorylation and impaired nuclear translocation. DHM treatment prevented the BTZ-induced ERK activation, and the protective effects of DHM were compromised by the ERK activator TBHQ. Importantly, DHM did not diminish the efficacy of BTZ against RPMI 8226 myeloma cells. This study demonstrates that DHM mitigates BTZ-induced toxicity on Schwann cells by restoring lysosome-autophagy activity through the ERK-TFEB pathway, highlighting DHM as a promising candidate for improving the adverse reaction of BTZ in the peripheral nervous system.