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Abstract
Fatigue is the most common and debilitating symptom of cytotoxic chemotherapy, yet its underlying neural mechanisms remain unclear. Peripheral inflammation induced by chemotherapy is a likely contributor, but how this translates into fatigue behavior is unknown, limiting effective interventions. Infection-induced fatigue in rodents is mediated by suppression of hypothalamic orexin signaling, a system essential for wakefulness and motivated behavior. Given that both infection and chemotherapy trigger peripheral inflammation and fatigue, we hypothesize that cytotoxic chemotherapy induces fatigue by disrupting orexin signaling. Understanding this pathway could reveal novel targets for reducing chemotherapy-related fatigue and improving patient quality of life.