PPP1R15B (protein phosphatase 1 regulatory subunit 15B) is a regulatory subunit that functions as a critical regulator of the integrated stress response (ISR) by controlling eIF2α phosphorylation levels. In unstressed cells, PPP1R15B maintains low eIF2α phosphorylation by promoting its dephosphorylation through the PP1 phosphatase complex 1. Mechanistically, PPP1R15B contains a substrate-recruitment module with three helical elements that captures the trimeric eIF2 complex, positioning it for PP1-mediated dephosphorylation despite eIF2B inhibition 2. This function is essential for maintaining normal protein synthesis and cellular homeostasis. PPP1R15B dysfunction causes severe disease. A homozygous R658C mutation, located within the PP1-binding site, impairs PPP1R15B-PP1 complex stability, resulting in chr1 ISR activation and causing microcephaly, short stature, intellectual disability, and developmental delay 34. The cognitive deficits directly result from sustained ISR activation impairing synaptic function and memory 4. PPP1R15B is also implicated in cancer drug resistance. In glioblastoma, multiple myeloma, and hepatocellular carcinoma, PPP1R15B is upregulated through super-enhancer acquisition and drives drug-tolerant persister cell programs by maintaining protein homeostasis and redox buffering 567. Pharmacological PPP1R15B inhibition potentiates chemotherapy and targeted therapy responses, suggesting therapeutic promise in overcoming resistance.