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Psilocybin prevents chemotherapy-induced peripheral neuropathy via mitochondrial trafficking preservation

ABSTRACT: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling complication affecting millions of patients and frequently limiting the delivery of life-saving cancer therapy, with no proven prophylactic options and only modest treatments for established symptoms. Here, we show that as little as two doses of psilocybin before the administration of chemotherapy robustly prevented the onset of CIPN across platinum- and taxane-based models, with effects remaining throughout repeated chemotherapy cycles, with no impact on efficacy in tumor-bearing mice. Central blockade of 5HT2A showed that psilocybin operates through dual mechanisms: peripherally, it preserved tactile sensitivity and protected intraepidermal nerve fiber endings, marking the first direct sensory neuron protection by a serotonergic psychedelic; centrally, it prevented the development of mechanical hypersensitivity in a 5HT2A-dependent manner, as evidenced by normalization of medial prefrontal cortical synaptic activity and cortical alpha/beta EEG power. Peripherally, in freshly excised human peripheral nerves, psilocybin restored axonal mitochondrial distribution, cristae structure, and directional motility; mechanistically, psilocybin activation of the TrkB-Akt-PAK5-MAP2-KIF5 pathway and remobilization of syntaphilinanchored mitochondria led to enhanced survivability of human induced pluripotent stem cell derived sensory neurons treated with chemotherapy. These results establish psilocybin as a first in-class prophylactic agent for CIPN and uncover a mechanistic link between serotonergic signaling in the peripheral nervous system and cellular metabolic resilience that stabilizes distal axonal energetics while also preserving central neural function. Given psilocybin’s established safety including in oncology settings, these discoveries support its urgent clinical evaluation as a transformative strategy to prevent CIPN.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE333441 | GEO | 2026/09/04

REPOSITORIES: GEO

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Project description:The microtubule-stabilizing drug paclitaxel remains standard of care for various solid malignancies but frequently leads to chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a leading cause for premature treatment termination and a significantly reduced quality of life in long-term cancer survivors. The molecular mechanisms of neuro-axonal degeneration, neuroinflammation and pain in patients treated with paclitaxel remain incompletely understood, and there are currently no predictive biomarkers or preventive treatments. We used human iPSC-derived sensory neurons exposed to paclitaxel to comprehensively model the pathophysiology of CIPN. Neurotoxicity was assessed over time using viability assays and sequential RNA sequencing as well as deep proteome and lipidomic analyses. We observed a time and dose-dependent decline of cell viability at clinically relevant paclitaxel doses. Sequential RNA sequencing defined JUN as an early immediate gene, followed by the overexpression of genes of the neuronal stress response (e.g., ARID5A, WEE1, DUSP16, GADD45A), neuronal injury and apoptotic pathways (e.g., ATF3, HRK, BBC3 [PUMA], BCL2L11 [BIM], CASP3), neuroinflammation and nociception (CALCB, MMP10, IL31RA, CYSLTR2, C3AR1, TNFRSF12A) and neuronal transduction (e.g., CAMK2A, STOML3), while key enzymes of lipid biosynthesis were markedly downregulated (e.g., LSS, HMGCS1, HMGCR, DHCR24). Deep proteome analyses following 48 hours of exposure to 100nM paclitaxel revealed a strong correlation of differentially expressed RNA with proteins, and a marked degradation of essential axonal transport proteins such as kinesins, stathmins and scaffold proteins. Consistent with the downregulation of rate-limiting enzymes of lipid biosynthesis, lipidome analysis confirmed deregulation of neuronal lipid homeostasis. In summary, paclitaxel induces transcriptomic and proteomic signatures of the neuronal stress response, neuroinflammation, nociception and disturbed metabolism. These may explain, in part, the clinical phenotype of sensory loss, hypersensitivity and neuropathic pain frequently observed in patients suffering from CIPN, but constitute pharmacologically addressable targets

Project description:The microtubule-stabilizing drug paclitaxel remains standard of care for various solid malignancies but frequently leads to chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a leading cause for premature treatment termination and a significantly reduced quality of life in long-term cancer survivors. The molecular mechanisms of neuro-axonal degeneration, neuroinflammation and pain in patients treated with paclitaxel remain incompletely understood, and there are currently no predictive biomarkers or preventive treatments. We used human iPSC-derived sensory neurons exposed to paclitaxel to comprehensively model the pathophysiology of CIPN. Neurotoxicity was assessed over time using viability assays and sequential RNA sequencing as well as deep proteome and lipidomic analyses. We observed a time and dose-dependent decline of cell viability at clinically relevant paclitaxel doses. Sequential RNA sequencing defined JUN as an early immediate gene, followed by the overexpression of genes of the neuronal stress response (e.g., ARID5A, WEE1, DUSP16, GADD45A), neuronal injury and apoptotic pathways (e.g., ATF3, HRK, BBC3 [PUMA], BCL2L11 [BIM], CASP3), neuroinflammation and nociception (CALCB, MMP10, IL31RA, CYSLTR2, C3AR1, TNFRSF12A) and neuronal transduction (e.g., CAMK2A, STOML3, PIRT), while key enzymes of lipid biosynthesis were markedly downregulated (e.g., LSS, HMGCS1, HMGCR, DHCR24). Deep proteome analyses following 48 hours of exposure to 100nM paclitaxel revealed a strong correlation of differentially expressed RNA with proteins, and a marked degradation of essential axonal transport proteins such as kinesins, stathmins and scaffold proteins. Consistent with the downregulation of rate-limiting enzymes of lipid biosynthesis, lipidome analysis confirmed deregulation of neuronal lipid homeostasis. In summary, paclitaxel induces transcriptomic and proteomic signatures of the neuronal stress response, neuroinflammation, nociception and disturbed metabolism. These may explain, in part, the clinical phenotype of sensory loss, hypersensitivity and neuropathic pain frequently observed in patients suffering from CIPN, but constitute pharmacologically addressable targets.

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Psilocybin prevents chemotherapy-induced peripheral neuropathy via mitochondrial trafficking preservation

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