ENO3 regulates ferroptosis by interaction with PKM2 to promote the progression of metabolic dysfunction-associated steatotic liver disease

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Cao-41-121-133-2026.pdf(13.12 MB)
Date
2026
Authors
Qian Hao
Xue Li
Jing Liu
Minghao Li
Baoding Li
Shengjuan Hu
Yanling Li
Xiaofei Li
Yuanyuan Tang
Fuliang Pan
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Universidad de Murcia, Departamento de Biologia Celular e Histiologia
Abstract
Background. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder characterized by excessive lipid accumulation in the liver. The glycolytic enzyme enolase 3 (ENO3) is reported to be most significantly elevated in the analysis of MASLD-related sequencing results based on the GEO database. However, the specific mechanism by which ENO3 regulates MASLD is not fully understood. Objective. To investigate the role and possible molecular mechanism of ENO3 in MASLD. Methods. The expression of ENO3 and PKM2 in the liver tissues of control and MASLD rats was detected by immunohistochemistry and western blot. In vitro studies involved treating THLE-2 cells with free fatty acids (FFA) and Ferrostatin-1 (Fer-1), as well as manipulating ENO3 expression via small interfering RNA (siRNA) and overexpression plasmids, and manipulating PKM2 expression via siRNA. Fat accumulation was assessed using Oil Red O staining and measurements of intracellular total cholesterol (TC) and triglycerides (TG). Ferroptosis markers, including SLC7A11, GPX4, Fe2+, and malondialdehyde (MDA), were evaluated. Protein-protein interactions between ENO3 and PKM2 were examined using co-immunoprecipitation (Co-IP) and immunofluorescence. Results. MASLD liver tissues exhibited significantly higher levels of ENO3 and PKM2. Silencing ENO3 in FFA-treated THLE-2 cells reduced fat accumulation, downregulated PKM2 expression, and decreased ferroptosis markers. Conversely, ENO3 overexpression promoted fat accumulation and ferroptosis, which were mitigated by Fer-1 or si-PKM2. Co-IP and immuno-fluorescence confirmed the physical interaction and co-localization of ENO3 and PKM2 in THLE-2 cells. Conclusions. ENO3 interacted with PKM2 to regulate ferroptosis and further promoted the progression of MASLD.
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Keywords
PKM2 , Ferroptosis , Metabolic dysfunction-associated steatotic liver disease (MASLD) , Fat accumulation , ENO3
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http://hdl.handle.net/10201/181749
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Histology and histopathology, Vol.41, Nº1, (2026)
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