Targeting chemobrain: from experimental models to therapeutic discovery

Chemotherapy-induced cognitive impairment affects a substantial proportion of cancer survivors and significantly diminishes quality of life, yet no FDA-approved therapies exist. Chemotherapeutic agents such as cisplatin, doxorubicin, paclitaxel and methotrexate induce oxidative stress, DNA damage, mitochondrial dysfunction and neuroinflammation, which disrupt synaptic plasticity and neurogenesis. Key pathways include PARP1 activation, NAD depletion, COX-2 signaling and adenosine A2A receptor dysregulation. Evidence from rodent and complementary models including Drosophila, zebrafish and Caenorhabditis elegans demonstrates conserved mechanisms. We highlight a multi-model discovery pipeline and discuss emerging therapeutic strategies targeting redox balance, mitochondrial function and neuroinflammatory pathways to mitigate cognitive decline in cancer survivors.