## 1 Cancer-Associated Cachexia Overview  
Cancer-associated cachexia (CAC) is a complex hypercatabolic syndrome characterised by an ongoing and involuntary loss of muscle mass and body weight, accompanied or not with the loss of adipose tissue, that cannot be reversed by nutritional supplementation, leading to progressive functional impairment [1]. Other physiological abnormalities including insulin resistance, loss of appetite or anorexia, asthenia, sarcopenia and anaemia are also included in the clinical traits of this comorbidity [2]. CAC is a multi-organ syndrome involving the brain [3,4], heart [5,6], liver [7,8], pancreas [9] and gut [10], which prompts systemic metabolic rewiring and systemic inflammation. However, the mechanisms of impairment occurring in these organs are understudied [11]. Overall, CAC is a burden affecting approximately 80% of cancer patients culminating in death in 20-30% of cases [12]. The prevalence of the comorbidity varies according to the cancer type and stage, reaching up to ~70% in pancreatic cancer, ~60% in gastroesophageal and head-neck cancers, 50-40%in lung, colorectal and certain haematological cancers and \(\sim\)15-25% in breast and prostate cancers [13]. Yet, regardless of the tumour location or stage, CAC is considered a negative prognostic factor [14]. Since chemotherapy dose is administered considering body surface area or lean body mass from the patient, cachexia reduces antitumor efficacy and tolerance to treatment, increases susceptibility to side effects and toxicity and therefore increases mortality in patients and reduces the disease's overall survival rate [15; 16]. The complexity and heterogeneity of this syndrome rely on the involvement of many mediators (such as systemic pro- and anti-inflammatory mediators, hormones, neuropeptides and tumour-derived factors) and signalling pathways, making the clinical management very challenging [17]. Despite representing a major burden in the cancer patients' quality of life the scientific knowledge of the disease is still scarce. The underlying pathophysiological mechanisms of this disorder are not completely understood, therefore, there are no approved standard treatments for CAC. Even so, in clinical practice, a comprehensive approach involving pharmacological interventions, nutritional supplementation and the recommendation of physical exercise is usually prescribed [18]. Studying the intertwining of dysregulated mechanisms during CAC could provide new therapeutic targets for the disease [19]. The most deleterious characteristic of CAC is the loss of skeletal muscle. This organ comprises almost half of the body weight and has an essential role in maintaining homeostasis, in whole-body energy production and protein metabolism, serving as a reservoir for amino acids sustaining protein synthesis [20]. Skeletal muscle mass is preserved due to an elaborate balance between protein anabolism and catabolism [21]. During tumour progression followed by frequent occurrence of CAC, this equilibrium is disrupted, resulting in acceleration of protein breakdown and decline of protein synthesis [22]. The loss of skeletal muscle is induced by the secretion of various pro-inflammatory and factors promoters of catabolism by immune and cancer cells such as proteolysis inducing factor (PIF), interleukin-1 (IL-1), IL-6, IL-8, tumour necrosis factor-\(\alpha\) (TNF-\(\alpha\)), myostatin, angiotensin II and activin A potentiating catabolism [23]. In combination these stimuli activate different signalling pathways involved in muscle wasting: ubiquitin-proteasome system (UPS), autophagy and calcium-activated protease calpains [24]. It is also noteworthy that during cachexia, the capacity for regeneration of muscle cells is damaged [25]. Simultaneously, it also accounts for muscle wasting and the decrease in pro-anabolic signals including insulin, insulin-like growth factor-1 (IGF-1), growth hormone and cytokines hampering inflammation namely interleukin-4 (IL-4) and interleukin-10 (IL-10) [24].