{"doi":"10.3390/antiox13070850","title":"Novel Inhibitor of Keap1-Nrf2 Protein–Protein Interaction Attenuates Osteoclastogenesis In Vitro and Prevents OVX-Induced Bone Loss In Vivo","abstract":"Keap1 interacts with Nrf2 by assisting in its ubiquitination and subsequent proteolysis. By preventing ROS accumulation during RANKL-induced osteoclastogenesis, Nrf2 activation can prevent the differentiation of osteoclasts. Additionally, inhibiting the Keap1-Nrf2 PPI can be an effective strategy for triggering Nrf2 to regulate oxidative stress. Structure-based virtual screening was performed to discover a potentially novel Keap1-Nrf2 PPI inhibitor wherein KCB-F06 was identified. The inhibitory effects of KCB-F06 on osteoclastogenesis were investigated in vitro through TRAP staining and bone resorption assays. An ovariectomy-induced osteoporosis mouse model was applied to evaluate KCB-F06's therapeutic effects in vivo. Lastly, the underlying mechanisms were explored using real-time PCR, Western blotting, and co-IP assays. KCB-F06 was discovered as a novel Keap1-Nrf2 PPI inhibitor. As a result, the expression of antioxidants (HO-1 and NQO1) was suppressed, hence reducing ROS accumulation during osteoclastogenesis. Subsequently, this caused the inactivation of RANKL-induced IKB/NF-kB signaling. This eventually led to the downregulation of osteoclast-specific proteins including NFATc1, which is an essential transcription factor for osteoclastogenesis. These results demonstrated that Nrf2 activation in osteoclasts is a valuable tool for osteoclastic bone loss management. In addition, KCB-F06 presents as an alternative candidate for treating osteoclast-related bone diseases and as a novel small molecule that can serve as a model for further Keap1-NRF2 PPI inhibitor development.","journal":"Antioxidants","year":2024,"id":436993,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1246382,"name":"Hongyuan Yao","orcid":null,"position":1,"is_corresponding":false},{"id":1246383,"name":"Alessandra Marie Encarnacion","orcid":null,"position":2,"is_corresponding":false},{"id":1246384,"name":"Jujin Jeong","orcid":null,"position":3,"is_corresponding":false},{"id":1246385,"name":"Yunju Choi","orcid":null,"position":4,"is_corresponding":false},{"id":1246386,"name":"Sang-Wook Park","orcid":null,"position":5,"is_corresponding":false},{"id":1245801,"name":"Sunwoo Lee","orcid":"0000-0001-5079-3860","position":6,"is_corresponding":false},{"id":1001700,"name":"Tae‐Hoon Lee","orcid":"0000-0003-0105-1750","position":7,"is_corresponding":false},{"id":870235,"name":"Zhihao Chen","orcid":"0000-0003-0128-1409","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:00:29.872940Z","pmid":"39061918","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":[]}