Fig. 9

A schematic representation of the EGFR/ProT/NF-κB/HOTAIR axis involved in cisplatin-induced cancer cachexia. In bladder cancer patients receiving cisplatin chemotherapy, cisplatin induces EGFR phosphorylation and activation, leading to upregulation of ProT expression. Excess ProT enhances NF-κB phosphorylation and acetylation [30], thereby increasing its transcriptional activity. Phosphorylated NF-κB translocates to the nucleus, where it binds to the promoter region of HOTAIR and transactivates HOTAIR expression. In addition, HOTAIR facilitates IκBα degradation and thus enhances NF-κB activation, thereby creating a feed-forward regulatory circuit between NF-κB and HOTAIR [25]. Subsequently, excess HOTAIR upregulates expression of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β, resulting in cancer cachexia. We used EGFR inhibitors (gefitinib and erlotinib), NF-κB inhibitors (JSH-23 and TPCA-1), human ProT overexpression and knockdown, as well as human HOTAIR overexpression and CRISPRi-mediated mouse Hotair knockdown to dissect this signaling axis. The pathways in gray color have been reported previously