Tristetraprolin attenuates schistosomiasis-induced liver fibrosis through m⁶A-mediated regulation of TGF-β1 mRNA stability

Inhibiting the activation of hepatic stellate cells (HSCs) represents a key therapeutic strategy for alleviating liver fibrosis induced by schistosomiasis. Diverse cell populations secrete pro-inflammatory cytokines and chemokines, which induce HSC activation and thereby promote hepatic fibrosis progression. Tristetraprolin (TTP) exerts a pivotal role in the post-transcriptional regulation of pro-inflammatory cytokines by either accelerating mRNA degradation or suppressing translation, a regulatory mechanism closely associated with the pathogenesis of various hepatic disorders. However, the pathological roles of TTP in Schistosoma japonicum -induced liver fibrosis remain largely elusive. Here, we report that TTP is upregulated in the liver during S. japonicum -induced liver fibrosis, and its overexpression markedly ameliorates this fibrotic pathology in vivo . We further identify that TTP negatively regulates TGF-β1 mRNA stability by promoting N6-methyladenosine (m 6 A) RNA methylation, thereby inhibiting HSC activation. Mechanistically, TTP enhances transcription of the WT1-associated protein ( WTAP ) gene through its interaction with SMAD2/3. Furthermore, treatment with an m 6 A RNA methylation inhibitor confirms that TTP-mediated protection against S. japonicum -induced liver fibrosis, an effect associated with increased m⁶A RNA methylation in vivo . Thus, our findings uncover a novel and critical role of TTP in exerting its anti-fibrotic function via the WTAP/m 6 A epitranscriptomic machinery in the pathogenesis of S. japonicum -induced liver fibrosis. This finding provides a rationale for the therapeutic targeting of TTP-mediated m 6 A RNA methylation in S. japonicum -induced liver fibrosis. Activation of hepatic stellate cells (HSCs) represents a pivotal event in the progression of schistosomiasis-induced liver fibrosis. Pro-inflammatory cytokines and chemokines secreted by injured hepatocytes and activated macrophage induce HSC activation. However, the underlying mechanisms governing the fine-tuned regulation of pro-inflammatory cytokines and chemokines gene expression during the progression of schistosomiasis-induced liver fibrosis remain largely elusive. As a key negative regulator of immune responses, the role of TTP in liver fibrosis remains controversial. Furthermore, while TTP has been reported to act as a transcriptional co-regulator and modulate gene expression at the transcriptional level, the majority of TTP-related studies have centered on its canonical role as a key mediator of mRNA degradation. Here, our study demonstrates that TTP attenuates S. japonicum -induced liver fibrosis via the regulation of TGF-β1 mRNA stability in an m 6 A-dependent manner. Specifically, WTAP-mediated m⁶A RNA methylation of TGF-β1 mRNA exerts a suppressive effect on HSC activation, thereby mitigating S. japonicum -induced liver fibrosis. Notably, our findings uncover a previously uncharacterized regulatory mechanism whereby TTP promotes WTAP transcription via direct interaction with SMAD2/3. These results demonstrate that TTP-driven transcriptional regulation of WTAP represents a novel mechanism underlying HSC activation, and further identify a potential strategy for intervening in S. japonicum -induced liver fibrosis.