Methyltransferase METTL1 Upregulates USF2 in a m7G-Dependent Manner to Accelerate Septic Cardiomyopathy by Inactivating PINK1/Parkin-Mediated Mitophagy.

Authors

Wei Dong, Jin Chen, Zhiping Xiong, Ruichun Liao, Junfei Weng, Zhichao Wang, Xiaoping Peng

Published in

Cardiovascular toxicology. Volume 26. Issue 8. Jul 23, 2026. Epub Jul 23, 2026.

Abstract

Septic cardiomyopathy (SCM) is a severe complication of sepsis, characterized by high mortality. The activation of mitophagy in cardiomyocytes is crucial for alleviating SCM. The N7-methylguanosine (m7G) modification mediated by methyltransferase 1 (METTL1) is known to negatively regulate mitophagy. This study investigated the mechanism of METTL1 in the mitophagy of cardiomyocytes in SCM. Human cardiomyocytes (HCMs) were stimulated with lipopolysaccharide (LPS) to establish the SCM model. C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to create a septic model. Mitophagy was assessed utilizing the mt-Keima assay, while mitochondrial membrane potential was measured with the JC-1 assay. MitoSOX Red assay was employed to evaluate levels of mitochondrial reactive oxygen species (ROS). The interaction between METTL1 and upstream transcription factor 2 (USF2), as well as between USF2 and PTEN-induced putative kinase protein 1 (PINK1), was confirmed through RNA immunoprecipitation (RIP) and RNA pull-down or dual luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays. The silenced METTL1 mitigated LPS-triggered myocardial damage in vitro. The inhibition of mitophagy nullified the protective effects conferred by METTL1 silencing in LPS-induced HCMs. Consistently, METTL1 silencing ameliorated myocardial injury induced by sepsis in a mouse model. METTL1 enhanced the expression of USF2 in an m7G-dependent manner. USF2, in turn, inactivated the PINK1/Parkin signaling pathway by repressing PINK1 transcription. The repression of USF2 negated the protective effects of METTL1 silencing on myocardial damage and mitophagy. METTL1 aggravated myocardial injury by inhibiting PINK1/Parkin-mediated mitophagy through the upregulation of USF2 in a m7G-dependent manner in SCM models, thereby identifying METTL1 as a potential therapeutic target for SCM.

PMID:
42490034
Bibliographic data and abstract were imported from PubMed on 23 Jul 2026.

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