{"doi":"10.3390/ijms21062064","title":"Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts","abstract":"The sphingosine kinase 1 (SPHK1)/sphingosine–1–phosphate (S1P) signaling axis is emerging as a key player in the development of idiopathic pulmonary fibrosis (IPF) and bleomycin (BLM)-induced lung fibrosis in mice. Recent evidence implicates the involvement of the Hippo/Yes-associated protein (YAP) 1 pathway in lung diseases, including IPF, but its plausible link to the SPHK1/S1P signaling pathway is unclear. Herein, we demonstrate the increased co-localization of YAP1 with the fibroblast marker FSP1 in the lung fibroblasts of BLM-challenged mice, and the genetic deletion of Sphk1 in mouse lung fibroblasts (MLFs) reduced YAP1 localization in fibrotic foci. The PF543 inhibition of SPHK1 activity in mice attenuated YAP1 co-localization with FSP1 in lung fibroblasts. In vitro, TGF-β stimulated YAP1 translocation to the nucleus in primary MLFs, and the deletion of Sphk1 or inhibition with PF543 attenuated TGF-β-mediated YAP1 nuclear localization. Moreover, the PF543 inhibition of SPHK1, or the verteporfin inhibition of YAP1, decreased the TGF-β- or BLM-induced mitochondrial reactive oxygen species (mtROS) in human lung fibroblasts (HLFs) and the expression of fibronectin (FN) and alpha-smooth muscle actin (α-SMA). Furthermore, scavenging mtROS with MitoTEMPO attenuated the TGF-β-induced expression of FN and α-SMA. The addition of the S1P antibody to HLFs reduced TGF-β- or S1P-mediated YAP1 activation, mtROS, and the expression of FN and α-SMA. These results suggest a role for SPHK1/S1P signaling in TGF-β-induced YAP1 activation and mtROS generation, resulting in fibroblast activation, a critical driver of pulmonary fibrosis.","journal":"International Journal of Molecular Sciences","year":2020,"id":52898,"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":125,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":268430,"name":"Tara Sudhadevi","orcid":"0000-0001-6966-6298","position":1,"is_corresponding":false},{"id":268431,"name":"Panfeng Fu","orcid":"0000-0001-8813-9258","position":2,"is_corresponding":false},{"id":269567,"name":"Prasanth-Kumar Punathil-Kannan","orcid":null,"position":3,"is_corresponding":false},{"id":268432,"name":"David L. Ebenezer","orcid":"0000-0001-7915-1159","position":4,"is_corresponding":false},{"id":252964,"name":"Ramaswamy Ramchandran","orcid":null,"position":5,"is_corresponding":false},{"id":269568,"name":"Vijay Putherickal","orcid":null,"position":6,"is_corresponding":false},{"id":269569,"name":"Paul Cheresh","orcid":null,"position":7,"is_corresponding":false},{"id":268433,"name":"Guofei Zhou","orcid":"0000-0002-5457-6705","position":8,"is_corresponding":false},{"id":268434,"name":"Alison W. Ha","orcid":"0009-0007-5385-915X","position":9,"is_corresponding":false},{"id":268435,"name":"Anantha Harijith","orcid":"0000-0002-4868-3862","position":10,"is_corresponding":false},{"id":252965,"name":"David W. Kamp","orcid":null,"position":11,"is_corresponding":false},{"id":250601,"name":"Viswanathan Natarajan","orcid":"0000-0002-5132-8212","position":12,"is_corresponding":false},{"id":241661,"name":"Long Shuang Huang","orcid":"0009-0007-3716-6118","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-18T20:43:25.742124Z","pmid":"32192225","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":[]}