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Figure 2. Major mechanisms of PSMD14-mediated tumor drug resistance. Based on its substrate specificity, PSMD14 promotes resistance to various therapeutic modalities through distinct signaling pathways. In the context of chemotherapy resistance, PSMD14 promotes cisplatin resistance by stabilizing E2F1 in head and neck squamous cell carcinoma, which maintains cancer stemness; enhances resistance to oxaliplatin and DAPT by stabilizing the ALK2 receptor in colorectal cancer, which activates the BMP6 signaling pathway and upregulates ABC transporters; and drives temozolomide resistance by stabilizing IMPDH2 in glioblastoma, which sustains de novo purine synthesis and mitochondrial function. In the context of targeted and endocrine therapy resistance, PSMD14 promotes anlotinib resistance by activating the PI3K/Akt/mTOR pathway in osteosarcoma, and enhances tamoxifen resistance by stabilizing ERα in breast cancer, which potentiates estrogen signaling transcription. In the context of proteasome inhibitor resistance, PSMD14 drives bortezomib resistance in multiple myeloma by functioning as a histone deubiquitinase (H2AK119ub) and cooperating with NSD2 to activate RELA/NF-κB transcription. Created in BioRender. Liu, H. (2026) https://BioRender.com/k88t3mg. ABC: ATP-binding cassette; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; mTOR: mechanistic target of rapamycin; ERα: estrogen receptor α; NSD2: nuclear receptor binding SET domain protein 2; RELA: RELA proto-oncogene, NF-κB subunit; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells.