PTRH2 (peptidyl-tRNA hydrolase 2) is a highly conserved mitochondrial protein with dual roles in translation and cell survival. During protein synthesis, PTRH2 releases peptidyl-tRNAs from the ribosome, facilitating translation termination. Beyond this canonical function, PTRH2 regulates adhesion-dependent signaling by modulating PI3K/AKT and ERK pathways and controlling Bcl2 expression, thereby influencing cell survival, anoikis resistance, and differentiation. Biallelic mutations in PTRH2 cause infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD), characterized by progressive neurological decline. Affected individuals commonly present with motor delay (92%), peripheral neuropathy (90%), distal weakness (86.4%), intellectual disability (84%), sensorineural hearing impairment (80%), and ataxia (79%) 1. Disease severity correlates with variant type: nonsense mutations typically produce more severe manifestations, while the frequent Q85P missense variant shows milder phenotypes 12. PTRH2 loss in Purkinje cells leads to mTOR pathway downregulation and progressive cerebellar atrophy with functional deficits 3, while PTRH2 mutations disrupt integrin-mediated signaling in skeletal muscle, causing congenital myopathy 4. Conversely, PTRH2 promotes cancer cell survival and anoikis resistance in pancreatic ductal adenocarcinoma, making it a potential therapeutic target; blocking PTRH2 expression alongside other antiapoptotic regulators enhances chemotherapy sensitivity 5.