인문학
사회과학
자연과학
공학
의약학
농수해양학
예술체육학
복합학
DBpia AI
AI 에이전트
AI 아이디어
AI 리더
AI 뷰어
Citeasy
크롬 서지관리 다운로드
지원사업
학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
커뮤니티
연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
초록·키워드
Metabolic dysfunction-associated steatohepatitis (MASH) is one of the fastest-growing chronic liver diseases and is characterized by excessive steatosis, inflammation, and progressive liver injury. The hepatitis B virus (HBV) X protein (HBx) is a major viral factor that contributes to the onset and progression of MASH. Emerging evidence highlights the role of epigenetic modifications, particularly N6-methyladenosine (m6A), as prevalent modifications of mRNAs that play crucial roles in MASH pathogenesis by regulating mRNA stability, translation, processing, and nuclear export. However, the epigenetic mechanisms by which m6A modification contributes to HBx-related MASH remain poorly defined. In this study, we observed that NOD-like receptor protein 3 (NLRP3)-dependent pyroptosis and intracellular lipid accumulation are markedly elevated in the livers of HBx-transgenic (HBx-Tg) mice in vivo and in HBx-expressing hepatocytes in vitro, exacerbating liver injury and driving MASH progression. Integrated metabolomic and transcriptomic analyses of HBx-Tg mice revealed distinct gene expression alterations, suggesting a key role for m6A modification in mediating hepatic inflammation and lipotoxicity. Mechanistically, we identified methyltransferase-like 3 (METTL3) as a critical positive regulator of this process. HBx upregulated METTL3 expression and the m6A level of NLRP3 mRNA in HBx-expressing hepatocytes, whereas METTL3 knockdown or catalytic inactivation suppressed NLRP3-dependent pyroptosis. Further investigation revealed that METTL3 enhances NLRP3 mRNA stability via m6A modification at A2748 site in the coding sequence. Moreover, the protein phosphatase 2A (PP2A) B56α subunit was found to interact with the METTL3 methyltransferase domain (MTD), facilitating its enzymatic activity and further increasing NLRP3 m6A methylation, thereby promoting pyroptosis and lipid accumulation in HBx-expressing hepatocytes. Importantly, treatment with STM2457, a selective inhibitor targeting the METTL3 MTD, significantly attenuated hepatic inflammation, steatohepatitis, and lipotoxicity. Taken together, our findings advance the understanding of HBx-induced hepatic lipid accumulation, steatosis, inflammasome formation, and pyroptosis, and indicate that targeting METTL3 with STM2457 intervention is a promising approach for MASH treatment.
인공지능 문자 인식 모델을 통해 추출된 텍스트로, 일부 오타나 오류가 포함될 수 있으나 지속적으로 개선 중입니다.
오류를 발견하셨다면 해당 부분을 드래그한 후 ' 를 통해 신고해주세요.
오류를 발견하셨다면 해당 부분을 드래그한 후 ' 를 통해 신고해주세요.
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