Fig. 7
From: Cancer cachexia: molecular basis and therapeutic advances
Inflammatory ligand-activated signaling pathways in cachexia-related muscle and fat atrophy. In patients with cachexia, elevated cytokine levels activate or inhibit multiple signaling pathways, leading to muscle and fat wasting. IL-1, IL-6, and TNF-α stimulate the release of CRH in the hypothalamus, which promotes the secretion of glucocorticoids through the HPA axis. This process inhibits the Akt signaling pathway while upregulating the expression of MuRF1, MAFbx, and autophagy-related genes. IL-1 and TNF-α recruit TRAF2/6 to activate the MAPK and NF-κB signaling pathways, facilitating the nuclear translocation of p38 MAPK and NF-κB, respectively, which upregulates the expression of MuRF1 and MAFbx. The TGF-β family engages its receptors, recruiting TRAF4/6 and Smad2/3 to activate the NF-κB and Smad signaling pathways. This promotes the nuclear translocation of the NF-κB and Smad2/3/4 complexes, increasing the expression of MuRF1 and MAFbx. The IL-6 family binds to its receptors to activate the JAK/STAT signaling pathway, leading to the nuclear translocation of STAT3 and the subsequent upregulation of MuRF1 and MAFbx expression. Moreover, the nuclear translocation of p38 MAPK and STAT3 induced by IL-1, TNF-α, and the IL-6 family can also upregulate UCP-1 expression, contributing to fat wasting through mitochondrial involvement. Additionally, the IL-1-, TNF-α-, and IL-6-mediated FoxO and STAT3 pathways directly participate in ATGL- and HSL-dependent lipolysis. This figure was created with BioRender (https://biorender.com)
