Cinnamic Acid Resolves Ageing-Biased Neuropathic Pain by Targeting a Glial GLRX3 Redox Switch
Chronic oxaliplatin-induced peripheral neuropathy (OIPN) is a common dose-limiting toxicity of chemotherapy, particularly in older adults, but mechanism-based therapies remain unavailable. Here, in a prospective, randomized, double-blind, placebo-controlled cohort, AC591 reduced the burden of chronic OIPN, with the strongest benefit in patients aged 60 years or older. In aged mice, AC591 restored dorsal root ganglion protein S-glutathionylation, especially in satellite glial cells, and relieved mechanical and cold hypersensitivity. DRG biodistribution profiling identified cinnamic acid (CA) as the principal AC591-derived component enriched in DRG. CA selectively inhibited glutaredoxin-3 (GLRX3), directly engaged GLRX3 in satellite glial cells, and covalently bound Cys148. Pharmacologic and genetic studies showed that CA-mediated GLRX3 inhibition restored S-glutathionylation on two downstream effectors.