Ribotoxic Stress Response: Coordinating Pyroptosis and Apoptosis

Ribotoxic stress response (RSR) is a translation-linked stress pathway that emerges when ribosomes stall and collide. Its upstream trigger is the MAP3K/ZAKα, a leucine-zipper- and SAM-containing kinase that relays ribotoxic stress to downstream programs shaping metabolism, immune signaling, and cell-fate decisions. Increasing evidence suggests that RSR also connects two major forms of programmed cell death-apoptosis and pyroptosis-by coordinating signaling crosstalk that shapes death outcomes. Disruption of this regulatory axis is associated with chronic inflammatory disorders, immune dysfunction, and malignancy. Here, we summarize current knowledge on the molecular mechanisms through which RSR interfaces with apoptotic and pyroptotic pathways, and we discuss its roles in cellular homeostasis and disease. Clarifying how RSR regulates cell-death signaling could guide the development of targeted therapeutic strategies for conditions involving dysregulated inflammation and cell death.