{"doi":"10.1002/glia.24094","title":"<scp>SRI</scp>‐42127, a novel small molecule inhibitor of the <scp>RNA</scp> regulator <scp>HuR</scp>, potently attenuates glial activation in a model of lipopolysaccharide‐induced neuroinflammation","abstract":"Glial activation with the production of pro-inflammatory mediators is a major driver of disease progression in neurological processes ranging from acute traumatic injury to chronic neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. Posttranscriptional regulation is a major gateway for glial activation as many mRNAs encoding pro-inflammatory mediators contain adenine- and uridine-rich elements (ARE) in the 3' untranslated region which govern their expression. We have previously shown that HuR, an RNA regulator that binds to AREs, plays a major positive role in regulating inflammatory cytokine production in glia. HuR is predominantly nuclear in localization but translocates to the cytoplasm to exert a positive regulatory effect on RNA stability and translational efficiency. Homodimerization of HuR is necessary for translocation and we have developed a small molecule inhibitor, SRI-42127, that blocks this process. Here we show that SRI-42127 suppressed HuR translocation in LPS-activated glia in vitro and in vivo and significantly attenuated the production of pro-inflammatory mediators including IL1β, IL-6, TNF-α, iNOS, CXCL1, and CCL2. Cytokines typically associated with anti-inflammatory effects including TGF-β1, IL-10, YM1, and Arg1 were either unaffected or minimally affected. SRI-42127 suppressed microglial activation in vivo and attenuated the recruitment/chemotaxis of neutrophils and monocytes. RNA kinetic studies and luciferase studies indicated that SRI-42127 has inhibitory effects both on mRNA stability and gene promoter activation. In summary, our findings underscore HuR's critical role in promoting glial activation and the potential for SRI-42127 and other HuR inhibitors for treating neurological diseases driven by this activation.","journal":"Glia","year":2021,"id":175722,"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":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9584,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":707710,"name":"Abhishek Guha","orcid":"0000-0003-2767-9941","position":1,"is_corresponding":false},{"id":487621,"name":"Ying Si","orcid":null,"position":2,"is_corresponding":false},{"id":487619,"name":"Thaddaeus Kwan","orcid":null,"position":3,"is_corresponding":false},{"id":225592,"name":"Burt Nabors","orcid":"0000-0001-5926-2230","position":4,"is_corresponding":false},{"id":693909,"name":"Natalia Filippova","orcid":"0000-0003-2128-5511","position":5,"is_corresponding":false},{"id":693910,"name":"Xiuhua Yang","orcid":"0000-0002-4949-131X","position":6,"is_corresponding":false},{"id":717539,"name":"Anish S. Myneni","orcid":null,"position":7,"is_corresponding":false},{"id":717540,"name":"Shriya Meesala","orcid":null,"position":8,"is_corresponding":false},{"id":279113,"name":"Ashley S. Harms","orcid":"0000-0002-7054-2812","position":9,"is_corresponding":false},{"id":486683,"name":"Peter H. King","orcid":"0000-0001-9391-7464","position":10,"is_corresponding":false},{"id":717000,"name":"Rajeshwari Chellappan","orcid":"0000-0003-4520-5491","position":0,"is_corresponding":true}],"reference_count":91,"raw_metadata":null,"created_at":"2026-07-18T23:47:15.431199Z","pmid":"34533864","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":[]}