SLMO2 promotes chemoresistance in glioblastoma by regulating BNIP3-dependent mitophagy via the NF-κB/HIF-1α axis

SLMO2 is upregulated by chemotherapeutics and reduces GBM chemosensitivity. • SLMO2 mediates TMZ- and H 2 O 2 -induced mitophagy in GBM cells. • SLMO2 transcriptionally upregulates the mitophagy receptor BNIP3. • SLMO2 promotes BNIP3 via the ROS–NF-κB–HIF-1α signaling axis. Glioblastoma (GBM) is a highly aggressive malignancy, with chemoresistance acting as a major hurdle that severely limits clinical efficacy and long-term prognosis. Mitophagy, a core mechanism of mitochondrial quality control, enables tumor cells to adapt to chemotherapy-induced stress and maintain survival. However, its regulatory mechanism in GBM chemoresistance remains poorly understood. Here, we identify SLMO2 as a key factor mediating chemoresistance in GBM. Low-dose TMZ induces protective mitophagy, whereas SLMO2 knockdown abrogates this autophagic defense, thereby sensitizing GBM cells to TMZ-induced apoptosis. Mechanistically, TMZ treatment upregulates SLMO2, which potently activates HIF-1α signaling to transcriptionally drive BNIP3-mediated mitophagy, a process dependent on ROS-NF-κB signaling. Notably, this SLMO2-mediated cascade is also engaged under cisplatin-induced stress, indicating a broader role in chemoresistance. Collectively, our findings reveal that SLMO2 promotes chemoresistance in GBM by regulating BNIP3-mediated mitophagy. Targeting SLMO2 disrupts mitochondrial homeostasis by this process, offering a novel therapeutic strategy for enhancing chemosensitivity in GBM. Download: Download high-res image (228KB) Download: Download full-size image