Sodium arsenite induces hepatic stellate cells activation by m 6 A modification of TGF-β1 during liver fibrosis.

The compound known as Sodium arsenite (NaAsO ₂ ), which is a prevalent type of inorganic arsenic found in the environment, has been strongly associated with liver fibrosis (LF), a key characteristic of nonalcoholic fatty liver disease (NAFLD), which has been demonstrated in our previous study. Our previous research has shown that exposure to NaAsO ₂ triggers the activation of hepatic stellate cells (HSCs), a crucial event in the development of LF. However, the molecular mechanism is still unknown. N6-methyladenosine (m ⁶ A) modification is the most crucial post-transcriptional modification in liver disease. Nevertheless, the precise function of m ⁶ A alteration in triggering HSCs and initiating LF caused by NaAsO ₂ remains unknown. Here, we found that NaAsO ₂ induced LF and HSCs activation through TGF-β/Smad signaling, which could be reversed by TGF-β1 knockdown. Furthermore, NaAsO ₂ treatment enhanced the m ⁶ A modification level both in vivo and in vitro. Significantly, NaAsO ₂ promoted the specific interaction of METTL14 and IGF2BP2 with TGF-β1 and enhanced the TGF-β1 mRNA stability. Notably, NaAsO ₂ -induced TGF-β/Smad pathway and HSC-t6 cells activation might be avoided by limiting METTL14/IGF2BP2-mediated m ⁶ A modification. Our findings showed that the NaAsO ₂ -induced activation of HSCs and LF is made possible by the METTL14/IGF2BP2-mediated m ⁶ A methylation of TGF-β1, which may open up new therapeutic options for LF brought on by environmental hazards.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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