Decoding Chemobrain: Insights from Multi-omics Approaches

Chemotherapy-induced cognitive impairment, widely known as chemobrain, has emerged as a pressing concern as cancer incidence and treatment success continue to rise worldwide. Patients frequently report persistent deficits in memory, attention, affective regulation, and executive function, which significantly diminish quality of life. While early explanations emphasized psychological causes, evidence now supports a biological basis involving oxidative stress, neuroinflammation, synaptic alterations, and blood-brain barrier disruption. Yet, the precise molecular mechanisms remain incompletely understood, in part due to methodological limitations of conventional neuroscience approaches. Recent advances in multi-omics technologies have opened new avenues to dissect the complexity of chemobrain at genomic, transcriptomic, proteomic, metabolomic, and lipidomic levels. Studies employing both untargeted discovery workflows and targeted validation strategies have revealed convergent disruptions in mitochondrial function, neurotransmitter pathways, and inflammatory signaling, despite differences across chemotherapeutic agents. Integrative analyses further highlight how these molecular perturbations align with behavioural deficits observed in preclinical and clinical settings. This review synthesizes current multi-omics evidence, emphasizing not only the shared downstream neurotoxic pathways across diverse chemotherapies but also the variability introduced by experimental design, tissue selection, and validation practices. Importantly, multi-omics profiling underscores the need for combination neuroprotective strategies, as chemotherapy-induced cognitive impairment arises from intertwined molecular insults rather than a single pathway. By consolidating mechanistic insights from multi-omics, this review aims to inform biomarker discovery, therapeutic innovation, and ultimately the development of precision strategies to mitigate the burden of chemobrain in cancer survivors.