TEC-mediated tRF-31R9J regulates histone lactylation and acetylation by HDAC1 to suppress hepatocyte ferroptosis and improve non-alcoholic steatohepatitis

脂肪性肝炎 HDAC1型 乙酰化 肝细胞 组蛋白 表观遗传学 化学 生物 医学 癌症研究 脂肪肝 遗传学 内科学 组蛋白脱乙酰基酶 基因 疾病 体外
作者
Juanjuan Zhu,Xian Wu,Mao Mu,Quan Zhang,Xueke Zhao
出处
期刊:Clinical Epigenetics [BioMed Central]
卷期号:17 (1)
标识
DOI:10.1186/s13148-025-01813-3
摘要

Tectorigenin (TEC) is a monomer of anthocyanin, which we found exhibits hepatoprotective effects. tRNA-derived fragments (tRFs) and ferroptosis play important roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). Recent discoveries have revealed that histone lactylation and acetylation play a crucial role in connecting cellular metabolism and epigenetic regulation through post-translational modification of histones. However, it is unclear whether TEC improves NASH by regulating histone lactylation, acetylation and hepatocyte ferroptosis through tRFs. In this study, we demonstrated that TEC significantly inhibits free fatty acids-induced hepatocyte ferroptosis both in vitro and in vivo. We identified tRF-31R9J (tRF-31-R9JP9P9NH5HYD) involved in TEC regulation of ferroptosis in steatosis hepatocytes. Overexpression of tRF-31R9J suppressed hepatocyte ferroptosis and enhanced cell viability in steatosis HepG2 cells. Knockdown of tRF-31R9J partially counteracted the inhibitory effect of TEC on ferroptosis in hepatocytes. Mechanistically, tRF-31R9J recruited HDAC1 to reduce the levels of histone lactylation and acetylation modifications of the pro-ferroptosis genes ATF3, ATF4, and CHAC1, thereby inhibiting their gene expression. This study demonstrates that TEC-mediated tRF-31R9J inhibits hepatocyte ferroptosis through HDAC1-regulated histone delactylation and deacetylation, thereby improving NASH. These discoveries offer a theoretical foundation and new strategies for the medical management of NASH.

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