DDI2 encodes an aspartic protease with dual roles in protein quality control and DNA damage response. Its primary function involves cleaving NFE2L1/NRF1, a transcription factor that regulates proteasome subunit expression. DDI2 mediates cleavage of ubiquitinated NFE2L1 at Leu-104, promoting its release from the endoplasmic reticulum membrane and subsequent activation of proteasome gene transcription 12. This pathway is critical for cellular adaptation to proteasome inhibition and oxidative stress 3. DDI2 also functions in DNA replication stress responses, working with DDI1 to remove RTF2 from stalled replication forks and maintain genome integrity 4. The protease activity requires extensive ubiquitination of NFE2L1, with UBE4A serving as a key E3 ligase that primes NFE2L1 for DDI2-mediated processing 5. Clinically, DDI2 shows oncogenic properties in colorectal cancer, promoting metastasis and drug resistance 6, while DDI2 deficiency suppresses liver cancer progression by increasing oxidative stress 7. The HIV protease inhibitor nelfinavir can inhibit DDI2 activity, potentially sensitizing cancer cells to proteasome inhibitors and ferroptosis 23. These findings position DDI2 as a potential therapeutic target for cancer treatment strategies.