see also:

• neoplasia / cancer / tumours
• oncology
• anorexia nervosa / eating disorders

• “Most people with cancer die of cachexia caused by the cancer instead of the cancer itself”

• blocking IL-6 from binding to neurons in a part of the brain called the area postrema (AP) prevents cachexia in mice, this worked by either:¹⁾
  • neutralized IL-6 with custom antibodies
  • using CRISPR to reduce the levels of IL-6 receptors in AP neurons
• see also: interleukin-6 (IL-6)

• triggers muscle breakdown

• ADAMTSL4 is a protein secreted by tumours activates the TGF-β signaling pathway in muscle and fat tissue, thereby triggering a catabolic program and appears to be another driver of cachexia in cancer patients²⁾

• growth differentiation factor 15 (GDF15) is a stress hormone which can trigger nausea by binding to GFRAL receptors in the brainstem and is a potent anorectic factor
• sensitivity to GDF15 is the cause of hyperemesis gravidarum and serum levels can also be 10-100x higher than normal in patients with advanced cancers

• ubiquitin-proteasome system:
  • inflammatory signals massively up-regulate specific E3 ubiquitin ligases (such as MuRF1 and MAFbx), tagging muscle proteins for destruction
• suppressed protein synthesis:
  • the body inhibits normal muscle building by blocking translation initiation factors (like eIF2 and mTOR pathways)
• reduced regeneration:
  • chronic catabolism impairs the ability of satellite cells to repair and regenerate damaged muscle fibers

• lipolysis and fat browning:
  • white adipose tissue undergoes accelerated breakdown (lipolysis) and converts into metabolically active “brown” fat (browning), burning energy wastefully
• resting energy expenditure:
  • heightened sympathetic nervous system activity increases the body's baseline calorie demand, even while food intake drops

• hypothalamic signaling:
  • inflammatory mediators disrupt appetite centers in the brain, suppressing appetite-stimulating neuropeptide Y and increasing satiety signals like leptin

• cancer-induced systemic inflammation disrupts vagal tone via increased CCL2/CCR chemokine acting in the CNS
• this dysregulation leads to reduced acetylcholine release from vagal synapses and resulting depletion of hepatic HNF4α, a crucial transcription factor governing liver protein metabolism
• the resulting hepatic dysfunction amplifies systemic inflammation, driving the cachectic symptoms that afflict many cancer patients
• restoring vagal function by targeting the right cervical vagus nerve reestablished normal liver metabolism, reduced systemic inflammation, and alleviated cachexia's clinical manifestations ³⁾
• a 2026 study on mice suggests that lung cancer produces more local prostaglandin E2 which then activates vagal nerve activity via lung neurons which appears to mediate cachexia and this can be remedied by blocking PGE2 production or blocking the the vagal nerve ⁴⁾

• reduced intake which cannot match the body's catabolic losses:
  • profound anorexia from the above mechanisms and metabolic shifts
  • ongoing nausea from the above mechanisms
  • physical gut obstruction
  • metabolic shifts