Therapeutic interventions against symptoms or disease caused by the ribotoxic stressors: shiga toxin & doxorubicin

Ribotoxic stressors inhibit protein synthesis by damaging or interacting with the ribosome and trigger cellular stress responses, including activation of JNK and p38 SAPKs through the MAP3K ZAK. This dissertation identifies doxorubicin as a novel ribotoxic stressor that requires active translation to activate SAPKs. Given the relevance of ribotoxic stressors such as Shiga toxin (Stx) in human disease, the work also evaluates potential therapeutic strategies. A monoclonal antibody against Stx2 prevented lethality in a model of hemolytic‑uremic syndrome, while the ZAK‑targeting kinase inhibitors sorafenib and nilotinib blocked doxorubicin‑induced inflammatory and apoptotic signaling in noncancerous cells. Doxorubicin was further shown to activate the NALP3 inflammasome, leading to IL‑1β maturation and release. These findings improve understanding of ribotoxic stress signaling and highlight potential therapeutic avenues for diseases driven by ribotoxic stressors.