Targeting ALG3/FOXD1/BNIP3 Axis Prevents Mitophagy and Gemcitabine Resistance of Nasopharyngeal Carcinoma

Understanding the specific role and underlying mechanisms of mitophagy may provide therapeutic benefit to patients with nasopharyngeal carcinoma (NPC). Forkhead box D1 (<i>FOXD1</i>), is overexpressed in NPC. However, its roles in NPC progression and therapy resistance remain largely unknown. NPC tissues displayed increased <i>FOXD1</i> expression compared to paired non-tumor tissues, which correlated with worse overall survival (OS). Upregulation of <i>FOXD1</i> promoted NPC cell proliferation, colony formation, migration, invasion, and impaired sensitivity to GEM by enhancing mitophagy levels. Mechanistically, <i>FOXD1</i> promoted mitophagy in NPC cells by transcriptionally initiating BNIP3 expression. This enhanced mitophagy, in turn, promoted proliferation, invasion, and migration and reduced NPC cell sensitivity to gemcitabine (GEM). Most interestingly, Asn176 <i>N</i>-glycosylation of the FOXD1 protein increased its stability and nuclear localization, thereby transcriptionally activating <i>BNIP3</i> expression to promote mitophagy of NPC cells. ALG3 directly interacted with FOXD1 and induced this <i>N</i>-glycosylation. Targeting the ALG3/FOXD1/BNIP3 axis offers a promising therapeutic strategy to inhibit the progression of NPC, which highlighting the potential of therapeutics targeting ALG3 and FOXD1 for regulating mitophagy and overcoming GEM resistance.