Idiopathic pulmonary fibrosis(IPF),a chronic interstitial lung disease,is characterized by aberrant wound healing,excessive scarring and the formation of myofibroblastic foci.Although the role of alternative splicing(...Idiopathic pulmonary fibrosis(IPF),a chronic interstitial lung disease,is characterized by aberrant wound healing,excessive scarring and the formation of myofibroblastic foci.Although the role of alternative splicing(AS)in the pathogenesis of organ fibrosis has garnered increasing attention,its specific contribution to pulmonary fibrosis remains incompletely understood.In this study,we identified an up-regulation of serine/arginine-rich splicing factor 7(SRSF7)in lung fibroblasts derived from IPF patients and a bleomycin(BLM)-induced mouse model,and further characterized its functional role in both human fetal lung fibroblasts and mice.We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation.Mechanistically,we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase(PKM),leading to metabolic dysregulation and fibroblast activation.In vivo studies showed that fibroblastspecific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis.Importantly,through drug screening,we identified lomitapide as a novel modulator of SRSF7,which effectively mitigated experimental pulmonary fibrosis.Collectively,our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.展开更多
Breathing,an essential physiological process,enables the continuous exchange of gases necessary for maintaining internal metabolic balance.On average,an adult inhales and exhales roughly 10,000 to 12,000 L of air each...Breathing,an essential physiological process,enables the continuous exchange of gases necessary for maintaining internal metabolic balance.On average,an adult inhales and exhales roughly 10,000 to 12,000 L of air each day to sustain adequate oxygen levels1.The lungs,which serve as the body’s primary organs for gas exchange,possess a remarkable intrinsic capacity for self-repair and regeneration following injury2,3.展开更多
基金supported by the National Natural Science Foundation of China(U24A20645,32171127,82200070)the Scientific Fund Project of Heilongjiang Province(JQ2022H001,China)+1 种基金the Science and technology project of Xiamen Medical College(K2023-08,China)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-078,China).
文摘Idiopathic pulmonary fibrosis(IPF),a chronic interstitial lung disease,is characterized by aberrant wound healing,excessive scarring and the formation of myofibroblastic foci.Although the role of alternative splicing(AS)in the pathogenesis of organ fibrosis has garnered increasing attention,its specific contribution to pulmonary fibrosis remains incompletely understood.In this study,we identified an up-regulation of serine/arginine-rich splicing factor 7(SRSF7)in lung fibroblasts derived from IPF patients and a bleomycin(BLM)-induced mouse model,and further characterized its functional role in both human fetal lung fibroblasts and mice.We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation.Mechanistically,we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase(PKM),leading to metabolic dysregulation and fibroblast activation.In vivo studies showed that fibroblastspecific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis.Importantly,through drug screening,we identified lomitapide as a novel modulator of SRSF7,which effectively mitigated experimental pulmonary fibrosis.Collectively,our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.
文摘Breathing,an essential physiological process,enables the continuous exchange of gases necessary for maintaining internal metabolic balance.On average,an adult inhales and exhales roughly 10,000 to 12,000 L of air each day to sustain adequate oxygen levels1.The lungs,which serve as the body’s primary organs for gas exchange,possess a remarkable intrinsic capacity for self-repair and regeneration following injury2,3.
