Abstract / Summary
Cancer cachexia is a systemic wasting syndrome driven by tumor burden, chronic inflammation, disrupted nutrient handling, and neuroendocrine stress. Supportive nutrition, exercise, and symptom management rarely restore lean mass, function, or treatment tolerance once wasting is established. Ferroptosis, iron-dependent cell death caused by phospholipid peroxidation, may connect inflammatory iron redistribution, lipid remodeling, mitochondrial stress, and impaired antioxidant defenses. This review critically evaluates ferroptosis in cachexia from a tumor-host pharmacology perspective, distinguishing causal evidence from associated oxidative signatures. We highlight two experimentally supported mechanisms: neutrophil-derived lipocalin-2 in lung cancer cachexia and tumor exosomal miR-203a-3p in pancreatic cancer-associated muscle wasting. We also examine the paradox that tumor ferroptosis induction may weaken host-tissue resistance and worsen muscle and adipose loss. We propose a "split-ferroptosis" strategy combining tumor sensitization with host-protective iron modulation, lipid peroxide scavenging, endogenous defense reinforcement, and biomarker-guided patient selection to expand the tumor-host therapeutic index.