{"doi":"10.3389/fphar.2025.1722559","title":"The ubiquitination–autophagy axis in cancer therapy resistance: mechanistic insights and therapeutic opportunities","abstract":"<jats:p>Therapy resistance is a major challenge in cancer treatment. Growing evidences reveal that the interaction between ubiquitination and autophagy plays a key role in regulating resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. In this review, we systematically summarize recent studies that reveal how specific E3 ligases, deubiquitinating enzymes, and ubiquitin-like modifiers influence autophagic flux and modulate the tumor response. We focus on key regulatory circuits—such as the Tripartite-motif protein 65–miR-138-5p–Autophagy related 7 (TRIM65–miR-138-5p–ATG7)pathway in non-small cell lung cancer, the Cullin-RING Ligase 4(CRL4)–mitophagy signaling pathway in ovarian cancer, and the Ubiquitin Specific Peptidase 14–S-phase kinase-associated protein 2(USP14–Skp2) axis in B-Raf proto-oncogene (BRAF) inhibitor resistance—illustrating the dual regulatory functions of ubiquitin-dependent protein turnover and autophagy. Furthermore, we highlight how noncoding RNAs and the tumor microenvironment influence ubiquitination-modulated autophagy and contribute to immune resistance or DNA repair remodeling. Finally, we discuss potential therapeutic strategies, including Proteolysis Targeting Chimeras (PROTACs), dual E3 ligase/autophagy inhibitors, and autophagy flux modulators, to overcome resistance and enhance treatment efficacy across multiple cancer types. These insights establish the foundation for targeting the ubiquitin–autophagy network as a cohesive strategy to combat refractory cancer.</jats:p>","journal":"Frontiers in Pharmacology","year":2026,"id":621696,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1605576,"name":"Hanxi Yan","orcid":null,"position":1,"is_corresponding":false},{"id":449508,"name":"Yulin Liu","orcid":"0000-0002-2881-6939","position":2,"is_corresponding":false},{"id":1605577,"name":"Anqi Zeng","orcid":null,"position":3,"is_corresponding":false},{"id":1605579,"name":"Linjiang Song","orcid":null,"position":4,"is_corresponding":false},{"id":1605575,"name":"Hengrui Zhang","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The ubiquitination–autophagy axis in cancer therapy resistance: mechanistic insights and therapeutic opportunities","abstract":"Therapy resistance is a major challenge in cancer treatment. Growing evidences reveal that the interaction between ubiquitination and autophagy plays a key role in regulating resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. In this review, we systematically summarize recent studies that reveal how specific E3 ligases, deubiquitinating enzymes, and ubiquitin-like modifiers influence autophagic flux and modulate the tumor response. We focus on key regulatory circuits-such as the Tripartite-motif protein 65-miR-138-5p-Autophagy related 7 (TRIM65-miR-138-5p-ATG7)pathway in non-small cell lung cancer, the Cullin-RING Ligase 4(CRL4)-mitophagy signaling pathway in ovarian cancer, and the Ubiquitin Specific Peptidase 14-S-phase kinase-associated protein 2(USP14-Skp2) axis in B-Raf proto-oncogene (BRAF) inhibitor resistance-illustrating the dual regulatory functions of ubiquitin-dependent protein turnover and autophagy. Furthermore, we highlight how noncoding RNAs and the tumor microenvironment influence ubiquitination-modulated autophagy and contribute to immune resistance or DNA repair remodeling. Finally, we discuss potential therapeutic strategies, including Proteolysis Targeting Chimeras (PROTACs), dual E3 ligase/autophagy inhibitors, and autophagy flux modulators, to overcome resistance and enhance treatment efficacy across multiple cancer types. These insights establish the foundation for targeting the ubiquitin-autophagy network as a cohesive strategy to combat refractory cancer.","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41646943","pmcid":"PMC12868213","openalex_id":"https://openalex.org/W7125102733","authors":[],"funders":[],"total_grants":0,"fwci":15.3716,"citation_percentile":0.98102755,"influential_citations":0,"citation_trend":[{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://public-pages-files-2025.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1722559/pdf","host_type":"journal"},{"url":"https://public-pages-files-2025.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1722559/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3389/fphar.2025.1722559","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41646943","host_type":"repository"},{"url":"https://doaj.org/article/a691c5fb18af4317bcf1ab2ba90cb46b","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12868213","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12868213","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12868213?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Autophagy in Disease and Therapy","Ubiquitin and proteasome pathways","Protein Degradation and Inhibitors"],"mesh_terms":[],"keywords":["Autophagy","Ubiquitin","Ubiquitin ligase","Cancer therapy","Tumor microenvironment","Immune system","Signal transduction","Dual role","Targeted therapy","Ubiquitination","Chemotherapy","Radiotherapy","immune therapy","E3 Ligase","Therapy Resistance"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T15:38:09.679708Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}