Integrated lipidomics and computational analyses reveal cardiolipin dysregulation as a therapeutic target in bortezomib-induced peripheral neuropathy

Multiple myeloma (MM), a common blood cancer driven by abnormal plasma cells, is frequently treated with bortezomib (BTZ), which often triggers peripheral neuropathy (BIPN). While mitochondrial dysfunction is implicated in BIPN, the role of cardiolipin (CL) as a critical mitochondrial phospholipid remains unclear. Understanding CL dynamics could unveil mechanisms to improve MM therapy. Serum lipidomic profiling was performed on 37 MM patients (with/without BIPN) to identify BIPN-specific lipid signatures using machine learning. Pathway analysis highlighted disrupted metabolic pathways. Virtual screening of FDA-approved drugs targeting CL-related proteins (CLS1, PGS1, PLD6, PTPMT1) was conducted, followed by molecular dynamics (MD) simulations. BTZ-treated animal models validated lipidomic findings impacts. Lipidomics revealed significant mitochondrial CL dysregulation in BIPN patients. BTZ-treated mice exhibited reduced CL levels in blood and spinal cord tissues, alongside increased cytoplasmic CL and decreased mitochondrial CL in neurons. Prolonged BTZ exposure caused spinal nerve vacuolation and reduced β3-tubulin expression, indicating axonal damage. Virtual screening identified acarbose, hesperidin, diosmin, and NADH as top candidates targeting CLS1/PGS1, with MD simulations confirming stable binding of diosmin to PGS1. BTZ disrupts CL synthesis and transport, inducing mitochondrial dysfunction and neuronal damage. Our study identified CL abnormalities as an important contributor in the pathogenesis of BIPN and proposes repurposable drugs (e.g., diosmin) for therapeutic intervention. Animal model validation underscores the translational potential of targeting CL pathways to mitigate BIPN in MM patients. Further research could advance biomarker development and neuroprotective strategies for BTZ-treated individuals.