Centrosomal protein 72 deficiency exacerbates liver fibrosis induced by Schistosoma japonicum infection

Résumé fourni par la source

Abstract Background Hepatic fibrosis induced by Schistosoma japonicum ( S. japonicum ) infection is a major global public health concern. Centrosomal protein 72 (CEP72), a key regulator involved in maintaining cellular architecture and integrity, is significantly upregulated during the progression of hepatic fibrosis; however, its specific biological function in this pathological process remains largely elusive. This study was designed to elucidate the novel biological role of CEP72 in liver fibrosis, with a particular focus on the pathogenesis of S. japonicum -induced hepatic fibrosis. Methods Publicly available transcriptomic datasets of human hepatic fibrosis were analyzed, and the key findings were validated in two murine models of liver fibrosis ( S. japonicum infection and carbon tetrachloride (CCl 4 ) injection). To investigate the functional role of CEP72 in hepatic fibrogenesis, Cep72 knockout ( Cep72 −/− ) mice were employed. Histological staining was performed to evaluate liver pathological changes, fibrotic area, and granuloma size. Transcriptomic profiling, quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), and western blot analyses were performed to assess the fibrogenic and inflammatory responses in liver tissues. Results CEP72 expression was significantly elevated in both human fibrotic liver samples and murine models of hepatic fibrosis. Notably, CEP72 deficiency markedly exacerbated liver fibrosis, as evidenced by significantly increased granuloma size and enhanced collagen deposition in both S. japonicum -infected and CCl 4 -treated mice. Transcriptomic analysis revealed a global upregulation of pro-fibrotic and pro-inflammatory genes in the livers of Cep72 −/− mice compared with wild-type controls. These findings were further confirmed by qRT-PCR, IHC, and western blot analyses, which showed increased expression of fibrogenic markers, including α-smooth muscle actin and Collagen I. Mechanistically, loss of CEP72 promoted hepatic fibrogenesis by enhancing the expression of the transcription factor early growth response 1 (EGR1), which in turn upregulated tumor necrosis factor-α (TNF-α) transcription. Conclusions Collectively, our findings demonstrate that CEP72 functions as a key negative regulator of inflammation-driven hepatic fibrosis. CEP72 deficiency accelerates the progression of liver fibrosis through the EGR1–TNF-α signaling pathway. This study identifies a previously unrecognized protective role of CEP72 in hepatic fibrosis and highlights its potential as a novel therapeutic target for the treatment of S. japonicum -induced and other types of inflammation-associated liver fibrosis.

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