PJA1 (praja ring finger ubiquitin ligase 1) is an X-linked E3 ubiquitin ligase that plays critical roles in protein degradation and cellular regulation. The protein exhibits E2-dependent E3 ubiquitin ligase activity, binding to ubiquitin-conjugating enzyme UbcH5B and facilitating protein ubiquitination 1. PJA1 is abundantly expressed in brain regions including cerebellum, cerebral cortex, and frontal lobe, making it a candidate gene for X-linked mental retardation 1. Mechanistically, PJA1 promotes proteasomal degradation of multiple target proteins through K48-linked ubiquitination, including PGAM5 at lysine 88, which affects mitochondrial function and pyroptosis regulation 2. The enzyme also degrades glyoxalase I (GLO1) in ferroptosis-sensitive cancer cells, leading to methylglyoxal accumulation and enhanced cell death sensitivity 3. Disease relevance includes involvement in chemotherapy resistance, where PJA1 suppresses GSDME-mediated pyroptosis in nasopharyngeal carcinoma 2, and neurodevelopmental disorders, with recurrent variants associated with trigonocephaly and epilepsy 4. Additionally, PJA1 mediates astrocytic GPR30 effects on learning and memory by regulating Serpina3n levels 5. Clinically, PJA1 expression correlates with treatment outcomes in various cancers and neurodevelopmental conditions.