ALDH2 Suppresses Ferroptosis and Promotes Bortezomib Resistance in Multiple Myeloma Through the KEAP1‐NRF2 Feedback Loop

Resistance to bortezomib (BTZ) represents a major obstacle that limits the therapeutic efficacy and worsens the prognosis of multiple myeloma (MM). Ferroptosis, a form of regulated cell death triggered by excessive lipid peroxidation, has garnered increasing attention for anticancer intervention, yet the mechanisms underlying ferroptosis in MM remain enigmatic. Here, we confirmed that ALDH2 is upregulated in MM patients and that its altered expression is closely associated with BTZ resistance and poor prognosis. Functionally, ALDH2 promoted the proliferation, BTZ resistance, and ferroptosis resistance of MM cells, suggesting its oncogenic role. Mechanistically, ALDH2 competitively bound to KEAP1 and stabilized NRF2 by preventing its ubiquitin-proteasome-mediated degradation, thereby promoting the nuclear translocation of NRF2 and subsequent upregulation of GPX4, and in turn regulating ferroptosis, proliferation, and BTZ resistance in MM. In parallel, NRF2 bound directly to the promoter region of ALDH2 and further enhanced ALDH2 transcription, thus forming a positive feedback loop. Collectively, our findings reveal that the ALDH2/KEAP1/NRF2-GPX4 axis may serve as a key regulator of ferroptosis in MM and a promising therapeutic target for overcoming BTZ resistance.