ZHX2 inhibits diabetes-induced liver injury and ferroptosis by epigenetic silence of YTHDF2

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication of type 2 diabetes mellitus (DM). The transcription factor zinc fingers and homeoboxes 2 (ZHX2) has been implicated in the pathogenesis of chronic liver diseases, yet its precise role and underlying mechanism in DM-induced hepatic injury remain poorly elucidated. METHODS: To investigate this, we used a high-fat diet (HFD) and streptozotocin (STZ) administration to create a DM model in mice, while high glucose (HG) exposure was used to simulate DM in vitro. Through various experiments such as luciferase reporter assay, chromatin immunoprecipitation, RNA immunoprecipitation, and rescue experiments, we aimed to uncover the mechanisms involving ZHX2. RESULTS: Our findings revealed that ZHX2 was lower and YTHDF2 was higher in the livers of DM mice and HG-induced Huh7 cells. ZHX2 overexpression rescued DM-induced liver injury. ZHX2 overexpression also reversed DM-induced hepatic ferroptosis in vivo and in vitro. Mechanistically, YTHDF2 recognized m6A-modified ZHX2 mRNA and promoted its degradation. In turn, ZHX2 inhibited the transcription of YTHDF2 by binding to its promoter region. Knockdown of ZHX2 led to increased ferroptosis in Huh7 cells through activating YTHDF2-induced GPX4 and SLC7A11 degradation. CONCLUSION: These findings highlight the involvement of the ZHX2-YTHDF2-ferroptosis pathway in DM-induced liver injury and suggest that targeting this pathway may hold therapeutic potential for improving such injuries.