Lysophospholipid-TRPV1 interactions in chemotherapy-induced neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting side effect of first-line chemotherapeutics such as paclitaxel, for which effective treatments are currently unavailable. We found that plasma collected 24 h after paclitaxel administration enhanced sensory neuron activation. To identify potential mediators of this effect, we applied a broad LC-HRMS-based lipidomics approach to quantify plasma lipids in breast cancer patients before and 24 h after treatment. We observed significant elevations in lysophospholipids with 18:1 fatty acid chain, especially lysophosphatidylcholine (LPC) and lysophosphatidylglycerol (LPG) after paclitaxel treatment. Assessing their activity on sensory neurons revealed that these unsaturated lysophospholipids, but not their saturated counterparts, activated the transient receptor potential vanilloid 1 (TRPV1) channel, a key mediator of nociception. To investigate TRPV1-LPL interactions, we combined molecular dynamics simulations with targeted mutagenesis. Unlike LPC, which is zwitterionic due to its choline headgroup, LPG carries a negative charge and contains a glycerol headgroup instead. As a result of lacking a positive countercharge in its headgroup, LPG adopts a more tilted orientation within the vanilloid binding pocket (VBP) and forms stronger interactions with residues S510 and S512. Overall, the agonist's potency appears to depend on its interaction with and proximity to Y511, which was confirmed through electrophysiological recordings and calcium imaging using mutated hTRPV1 channels. These findings reveal lipid-channel interactions and provide mechanistic insight into endogenous lipid modulation of pain signaling in the context of paclitaxel-induced CIPN.